Abstract: Papaya (Carica papaya L.) plants exhibit three sex types, as female, male, and hermaphrodite. However, the segregation distortion caused by non-homozygous hermaphrodite plants has long hindered the achievement of the "all-hermaphrodite" commercial breeding goal. This review systematically traces the major breakthroughs in research on papaya sex differentiation, from classical genetics to molecular genomics. We summarize the sex types, floral morphology, and the classical single-gene triallelic hypothesis, and elaborate on the construction of physical maps of sex chromosomes, the delineation of sex determination regions, and the identification of key determining genes CpYYL (the YY/Y^hY^h-lethality gene) and CpMp (the long male peduncle control gene), which together revealed the intrinsic links between sex chromosome evolution and dioecy. We also expound that the large-scale population genomic resequencing has overturned the traditional single-origin hypothesis and, for the first time, reported the multiple independent origins of hermaphrodites, specifically, HSY1 and HSY3 independently originating from wild males MSY1 and MSY3, respectively, which reshaping our understanding of papaya sex chromosome evolutionary history. Furthermore, this review discusses sex reversal, hormonal regulation, epigenetic regulation, the current applications and prospects of molecular marker-assisted breeding, and transgenic and gene-editing technologies for sex control in papaya. We address existing challenges and highlight future key research directions, and aim to ultimately achieve the goal of "all-hermaphrodite" commercial breeding in papaya through genetic engineering approaches.