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.