The grape belongs to the genus Vitis L., which are divided into two subgenera, Euvitis Planch. and Muscadinia Planch. The Euvitis has 50 to 70 species, in which V. vinifera L. is a predominant species with hundreds of known commercial cultivars grown world wide. The Muscadinia (muscadine grapes) consists of only two to three species predominated by V. rotundifolia and only commercially cultivated in the southeastern United States. V. rotundifolia is known by its multiple resistance to almost all grape diseases and insects found on the Euvitis species, while the latter possesses good fruit characteristics that do not exist in muscadines. Attempts to produce rotundifolia-vinifera hybrids to combine good fruit quality and disease resistance of both into F1 hybrids have been made by grape breeders for many years. Limited success was reported when the V. vinifera was used as seed parents. This research extended the interspecific crosses beyond V. vinifera into other Euvitis species. Among the Euvitis species, A. aestivalis, V. cinerea, V. champinii, V. labrusca, V. monticola, V. nesbittiana, V. riparia, V. rupestris, V. thunbergii, V. quinguangularis, all with pistillate flowers, were used as female parents pollinated with V. rotundifolia pollen. Eight out of the 10 cross combinations except V. cinerea and V. thunbergii set fruits. However, most of the Euvitis-rotundifolia crosses had extremely low fruits set (<1% of pollinated flowers). The only exception was V. labrusca cv. Woodruff, which had very high percentage of fruit set (70%). Interestingly, the fruits of V. labrusca cv. Woodruff × rotundifolia were pathonocarpic that had only half size of regular fruits set from open pollination with pollen sources from other Euvitis species. In the reciprocal crosses, three pistillate V. rotundifolia cultivars, `Fry', `Higgins', `Jumbo', were used as female pollinated by pollen from Euvitis species. Limited fruit sets were found from the crosses of V. rotundifolia × V. shuttleworthii, V. cordifolia, V. rupestris, V. Piasezkii, V. quinquagularis. Results from this study indicated that hybridization between Euvitis and muscadinia species is indeed very difficult but it is possible, and some Euvitis species are cross more compatible with V. rotundifolia than the others.