Sexual hybrids between distantly related Solanum species can undergo endosperm failure, a post-zygotic barrier in inter-species hybridizations. This barrier is explained by the endosperm balance number (EBN) hypothesis, which states that parents must have corresponding EBNs for viable seed formation. Tests for inter-crossability were made involving the Mexican species Solanum pinnatisectum Dunal. (series Pinnatisecta, ApiApi, 1EBN), autotetraploids of this species, Solanum verrucosum Schlechtd. (series Tuberosa, AA, 2EBN), haploids (2x, 2EBN) of the South American S. tuberosum L. (series Tuberosa, A1A1A2A2, 4EBN), and F2 haploid-species hybrids with South American species (AA, 2EBN) S. berthaultii Hawkes, S. sparsipilum (Bitter.) Juz. and Bukasov and S. chacoense Bitter. The development of hybrid endosperms was investigated for these combinations by confocal microscopy with regard to cell-division timing and tissue collapse. Novel sexual diploid (AApi) and triploid (AApiApi) inter-series hybrids were generated from S. verrucosum x S. pinnatisectum crosses by using post-pollination applications of auxin. F1 embryos were rescued in vitro. The hybrid status of recovered plants was verified by microsatellite marker analysis, and the ploidy was determined by chromosome counting. The application of phytohormones in inter-ploidy S. pinnatisectum x S. tuberosum crosses, however, did not delay endosperm collapse, and embryos were not formed. Other diploid, 1EBN species tested in remote hybridizations with Group Tuberosum were S. cardiophyllum Lindl., S. trifidum Correll, and S. tarnii Hawkes and Hjert., series Pinnatisecta, and S. bulbocastanum Dunal., series Bulbocastana. Based on the analysis of post-zygotic reproductive barriers among isolated species of section Petota, we propose strategies to overcome such incompatibilities.