For nearly a century and a half, settlement west of the Allegheny Mountains was retarded by the rugged terrain and fear of the unknown. It was the demand for furs in Europe and the promotion of trade with the Indians that led to the earliest attempts to explore the region, by John Lederer, Thomas Batts and Robert Fallam, and Gabriel Arthur in the 17th century. In the first half of the 18th century, the trans-Allegheny was viewed for the first time as a settlement region, as the English colonial administration planned a strategy to compete with the French for control of the Ohio Valley.

The first attempt at settlement in what is now West Virginia in 1706 in the Shenandoah Valley, led by Swiss promoters Louis Michel and Baron Christopher de Graffenreid, failed because of territorial disputes between Virginia, Maryland, and Pennsylvania. In 1716, Gov. Alexander Spotswood and his Knights of the Golden Horseshoe claimed the Shenandoah region for England, with an eye to future development. There is evidence from the records of the Philadelphia Synod of the Presbyterian Church that there was a small settlement at "Potomoke," perhaps near Shepherdstown, in 1717, though it is uncertain on which side of the Potomac River the settlement was located. The earliest recorded settlement was that of Morgan Morgan, a Welshman who lived on Mill Creek near Bunker Hill in Berkeley County, beginning in 1731.

The earliest colonists, like Morgan, came through Pennsylvania to Western Virginia down the Valley of Virginia, a narrow corridor between the Blue Ridge and Allegheny mountains that funneled settlers to locations from western Maryland to the Carolinas. This route was used by most of those who came to Western Virginia in the years before the French and Indian War. Several German families, followers of Joist Hite, inhabited an area along the South Branch in Hampshire County in the early 1730s. Three Dutch brothers, Isaac, John, and Henry Van Meter, settled in Hardy County in the 1740s. These colonists, who had settled in the Fairfax Proprietary, had to buy or lease lands from Lord Fairfax.

In 1751, Andrew Lewis, surveyor for the Greenbrier Company, found Jacob Marlin and Stephen Sewell living in Pocahontas County, where they had been for two years. By the outbreak of the French and Indian War, some 50 families had settled in the Greenbrier Valley, including members of the Lewis, Renick, and Clendenin families. In August 1755, Indians attacked the Greenbrier settlements, killing and capturing more than two dozen colonists. The rest fled to safety across the Allegheny Mountains. Settlers filtering into the New River Valley in this period were also rebuffed. The Robert Files and David Tygart families first colonized the future location of Beverly in Randolph County in 1753. The next year, three German brothers, Israel, Samuel, and Gabriel Eckerlin, came to Dunkard Bottom in Preston County.

Most of these early colonists settled, legally or illegally, on lands granted to speculative land companies, such as the Ohio, Greenbrier, and Loyal companies. Expansive grants to these companies in the hundreds of thousands of acres dated from 1745. Most early settlers were killed, captured, or driven out of the forward settlements when war commenced, though dozens of families returned to Western Virginia as early as 1758, when the French were defeated in the upper Ohio Valley.

The Treaties of Hard Labor and Fort Stanwix with the Cherokee and Iroquois nations in 1768 increased the safety and quiet along the trans-Allegheny frontier. A few hardy individuals pushed the settlement line farther west, along the Monongahela River and its tributaries. John Simpson settled on the West Fork River in Harrison County in 1764 and Colonel Zackquill Morgan in Monongalia County in 1768. Colonists began returning to the Greenbrier Valley in 1769, including the Stuarts, Clendenins, Renicks, Donnallys, Lewises, and Keeneys. The Tygart Valley region was resettled in 1772; conspicuous families who settled there included the Stalnakers, Westfalls, Haddens, and Wilsons, who suffered from a dearth of crops the following year, called the "starving season."

In the years after the French and Indian War, another route of settlement was opened up, the Ohio River, fed by its conjoining tributaries, the Allegheny and Monongahela. Beginning in 1769, families descended the rivers and settled in the fertile bottomlands of the Ohio and its tributaries, the so-called "western waters." Among the first was Col. Ebenezer Zane and the allied families that came with him from Shenandoah County and settled at Wheeling Creek. The Joseph Tomlinson family, from Wills Creek, Maryland, colonized the Grave Creek settlement, now Moundsville, at about the same time. These early settlers came to the Ohio Valley in kinship-neighbor groups that migrated cohesively and sequentially to the region over a period of several years, the typical settlement pattern of the trans-Allegheny. Land speculators came early to the frontier, such as Col. George Washington and Dr. James Craik, who claimed tens of thousands of acres along the Ohio and its tributaries during a canoe trip in 1770. Washington was surprised to learn that much of the favorable land had already been claimed.

In the years leading up to the Revolutionary War, many other settlers came to the Ohio Valley. Walter Kelly, William Morris, and Thomas Bullitt came to live in the Kanawha Valley in the early 1770s. Isaac Williams, a Tomlinson in-law, cleared land across the Ohio from the mouth of the Muskingum River in 1775, later the site of Williamstown, near present Parkersburg. But with the coming of the Revolutionary War and the deterioration of peace with the Indians, most colonists along the Ohio removed their families to more secure settlements farther east.

It was in the decade and a half after the close of the Revolutionary War that settlers came by the thousands to Western Virginia and to Kentucky. Typical of the groups that came was the Capt. James Neal group that settled at Parkersburg, Wood County, in 1785. From that part of Monongalia County that became part of Pennsylvania in 1784, more than 40 of these associated families came sequentially over a period of 15 years. By the first national census in 1790, there were nearly 56,000 individuals living in what is now West Virginia. Only the interior and southern portion of the future state were unsettled at the turn of the 19th century.