This review describes three decades of introduction, agro-technology development, breeding and selection of Hylocereus species, known as pitaya or dragon fruit, as an example of a holistic program aimed to develop the horticultural potential of a perennial underutilized fruit crop. Interspecific homoploid and interploid crosses and embryo rescue procedures produced improved hybrids, some of which have been released to farmers. Molecular tools and morphological and phenological comparisons between the parental species and the resulting hybrids provided valuable information on dominant/recessive traits and on genetic relationships that could be exploited for further hybridizations. In addition, Hylocereus were crossed with species of the closely related genus Selenicereus, producing valuable intergeneric hybrids. In situ chromosome doubling resulted in the production of autopolyploid lines, from which an understanding of the effect of increased ploidy on fruit traits and metabolomic profiles was obtained. Gamete-derived lines were produced, adding to our biobank homozygote lines that were subsequently used for further hybridization. Spontaneous chromosome doubling occurred in haploid gamete-derived Hylocereus monacanthus lines and in interspecific interploid Hylocereus megalanthus × H. undatus hybrids obtained from an embryo rescue procedure, resulting in plants with double the expected ploidy. Challenging technical problems were addressed by the development of protocols for DNA isolation, flow cytometry, in situ chromosome doubling, androgenesis, gynogenesis and embryo rescue following interspecific and interploidy crosses. Current research leading to the development of genomics and molecular tools, including a draft genome of H. undatus, is also presented. Perspectives for further development of Hylocereus species and hybrids are discussed.