The Isabella grape has had a very mysterious past. Some have suggested that this Vitis Labrusca variety originated in the Carolinas around 1815 by random pollination of a native Vitis Labrusca grape and an unknown vinifera. Others have claimed that the grape was cultivated by the Cherokee Indians or that it is a cross between an unknown vinifera and muscadine grapes. Regardless of its origin, it was quickly adopted in New York and New England. In 1824, Deacon Elizah Fry successfully planted the first grapes in New York State – Catawba and Isabella. William Prince of Flushing, Long Island also secured the grape, purchasing vines from Mrs. Isabella Gibbs, the wife of George Gibbs, a merchant then living in Brooklyn; hence the name, Isabella. Originally the grape displayed the standard "grapey/foxy" taste and flavor associated with Labrusca grapes, but modern winemaking techniques have succeeded in removing this characteristic, resulting in a strawberry/boysenberry-like flavored wine

Over time, Isabella began to be replaced by Concord or other hardier and more productive Vinifera varieties, but has survived in a few dedicated vineyards. Ironically, while production of the grape is virtually non-existent in the United States, it remains very popular in the rest of the world, where it has over 50 aliases. In Hungary and Georgia it is known as Izabella, Seksarda in Croatia, Fragola in Italy and Australia, and Albany Surprise in New Zealand. Large acreages of this grape are grown in Brazil, Russia, and in Columbia where it is that country’s most widely planted variety.

Goose Watch Winery is one New York winery that continues to vinify Isabella. The winery decided to cultivate Isabella because of the grape’s long history in New York and the fact that the variety creates a distinctive Boysenberry-like aroma which separates it from other native varieties that are just "grapey". As a bonus, the Isabella grape retains strong name recognition in the Finger Lakes region, so visitors to the winery do not need to be cajoled to taste the wine as with other non-mainstream grapes. The winery produces a semi-sweet style Rosé of Isabella wine named after a popular wine that used to be produced by the Great Western Winery (now the Pleasant Valley Wine Company). Every vintage of this wine has won at least one gold medal and the current 2004 vintage won Gold and was named "Best Native American Varietal" at the 2005 NY Wine Classic.

Isabella is also produced at a few other American wineries that specialize in producing wine from Vitis Labrusca grape. Also in New York, Barrington Cellars produces a semi-sweet rosé wine and an Ice wine from the Isabella grape. A little southwest in North East Pennsylvania, Heritage Wine Cellars produces several Vitis Labrusca wines which include Isabella. And near Solomons Maryland, Cove Point Winery produces a blush wine from Isabella.