Hydrangea s. l., belonging to the up-market segment of ornamental cultivars, currently faces a renaissance in horticulture. Hence, novel molecular assisted breeding approaches are timely. Wide hybridization, i.e. crosses between distantly related species, has been shown to be problematic. Recent studies have considerably improved our knowledge of the phylogenetic relationships between the ornamental Hydrangea s. l. species. A fully resolved and highly supported phylogenetic tree is currently available, based on an extensive marker selection including 13 highly variable chloroplast markers. This robust phylogenetic framework includes the majority of widely cultivated Hydrangea s. l. species that have been the center of attention in a number of crossing projects. The present study is based on this highly supported phylogenetic hypothesis. Here, we aim to select the best candidates for future successful breeding projects, involving interspecific crosses of both closely and distantly related Hydrangea s. l. lineages. Therefore, we integrated the phylogenetic relatedness of potential parental lines along with genetic distances calculated from a wide plastid marker selection. Direct crosses between two species were found to be successful up to an average genetic distance of 0.01065, while failure could be expected at an average genetic distance of 0.01385 and higher. In order to overcome this genetic distance threshold, we propose Hydrangea arborescens, H. sargentiana, H. integrifolia, and H. seemannii as the best candidates for future bridge-cross projects with currently available fertile hybrids. We expect that our results will allow breeders to overcome long-standing wide crossing difficulties and motivate breeding initiatives of potential economic value.