The genus Xiphophorus is an important vertebrate model for investigating the etiology and genetics of both spontaneous and induced cancers. Xiphophorus are comprised of 23 species most of which can be crossed to produce fertile interspecies hybrid progeny. The Xiphophorus gene map is well developed and allows genetic associations to be studied among cohorts of progeny derived from backcrossing interspecies hybrid animals to one of the parental strains. In interspecies cross-progeny from select Xiphophorus backcrosses, ionizing radiation, ultraviolet light (UVB), and exposure to methylnitrosourea (MNU) have all been shown to induce tumors. Induced tumor types represented in various models include melanoma, fibrosarcoma, schwannoma, retinoblastoma, etc. The well-established backcross hybrid genetics make Xiphophorus fish an excellent system to study the contribution of DNA repair capability to induced tumorigenesis. DNA repair pathways represent multigenic traits that must be tightly regulated to insure genome fidelity. Herein we review initial DNA repair studies that assess repair capacities among different Xiphophorus species and interspecies hybrids. Assessment of both base excision repair (BER) and nucleotide excision repair (NER) have yielded consistent results indicating reduced DNA repair function in hybrid fish tissues. These data provide molecular support for potential reduced fitness in hybrid fish under conditions of environmental stress and may present a plausible explanation for absence of interspecies hybridization in sympatric environments. In addition, they support the role of direct DNA damage and its repair in the initiation of tumors in Xiphophorus hybrids.