Milkweed (Asclepias sp.) is an important pollinator genus across North America and is a host plant for many butterfly species, notably the monarch butterfly (Danaus plexippus). Commercial production of Asclepias is limited to a few species, because most species lack commercial traits, with minimal branching habit, excessive height, and minimal color variation. This study used a commercially viable Asclepias species, butterfly weed (Asclepias tuberosa L.), as a maternal parent and trialed three different pollination methods in an attempt to create interspecific hybrids. Pollination methods included a traditional method, a pollen–solution-based method, and a novel inverted pollinia method. The inverted pollinia method increased pollination success rates 4-fold among intraspecific crosses of A. tuberosa. When pollination methods were optimized, A. tuberosa was used as the maternal parent, and one-way crosses were made to seven other Asclepias species using the inverted pollinia method. Of the seven species used as pollen donors, four developed hybrid seed successfully: green milkweed (Asclepias hirtella Woodson), purple milkweed (Asclepias purpurascens L.), showy milkweed (Asclepias speciosa Torr.), and common milkweed (Asclepias syriaca L.). As germination methods vary significantly among Asclepias species, three methods of germination were trialed on seed developed via interspecific hybridizations: direct seeded, cold–moist stratification, and embryo rescue. Of the three methods, cold–moist stratification was superior to direct seeding and embryo rescue. This research is the first documented case of a controlled interspecific hybridization event among these species.