Interspecific hybridization among the three most economically important cultivated species of Cucurbita spp., Cucurbita pepo, C. moschata, and C. maxima can be made but not readily. By means of various pollination measures, different mating systems, and varying selection methods, nine advanced interspecific-bridge lines were developed, in which the crossing barrier among the species and the male sterility of the F1 and subsequent generations were overcome over a 12-year period from 1999 through 2011. Despite the considerable influence of parental cultigens and environmental factors on the incompatibility of interspecific crosses, the plant and population compatibility significantly increased when a backcross with a recurrent parent in the same species or a multiple-way cross with a parent in the different species was made. As the generations advanced, the percentage of fertile seeds (PFS) significantly increased in all the sib- and self-families. The four advanced interspecific-bridge lines out of nine not only have gained the normal crossability of interspecific hybridization, but also could eliminate the sexual obstacles of the subsequent generations. The results demonstrate that a two- or three-species bridge line with crossing compatibility can be created by two- or three-species recombination and continuous selection. More importantly, the breakthrough of the advanced interspecific-bridge lines could provide a powerful platform for breeders to transfer favorable traits freely among the species and create more valuable and unique types or varieties through a conventional breeding process.