Beyond their own commercial potential, highland papayas (Vasconcellea spp.) bear genes for resistances against important diseases, cold hardiness, and monoecy, which are absent from the common papaya genome. While the two genera share many morphological traits, strong reproductive barriers have considerably limited the success of introgression programs, imposing the use of special techniques for hybridizations. In fact, all cytogenetic and genetic studies have consistently shown that Vasconcellea is relatively distant from Carica as compared to other Caricaceae genera. A few years after the first breakthrough obtained in the field, the present chapter reviews the potential of the different highland papaya species as sources of genes for papaya improvement, the considerable experience accumulated in the different hybridization programs, the advantages of this difficult approach, and its current perspectives. It also stresses the need for further exploration within Vasconcellea and closer genera of the Caricaceae. After the successful introgression of papaya ring spot virus resistance from V. quercifolia, the combination of marker-assisted selection, new breeding schemes (e.g., bridging species), and a deeper knowledge of Caricaceae gene pools should give access to more genes of considerable interest to the papaya industry.