To avoid the ethical and logistical problems of studying carcinogen-induced tumorigenesis in humans, animal models are generally used. Ultraviolet radiation (UVR) exposure is a strong melanoma risk factor. Upon studying melanoma-prone transgenic mice across 70 different genetic backgrounds we found that some strains were resistant to the melanoma-accelerating effects of UVR, despite all strains incurring the same amount of UVR-induced DNA damage. We performed genome-wide linkage scans for quantitative trait loci influencing susceptibility and resistance to melanoma in these mice. Rapid onset spontaneous melanoma onset was explained by segregation of germline variants in Prkdc, a gene involved in detection and repair of DNA damage. In contrast, rapid onset UVR-induced onset was linked to the Rrp15 gene, which encodes a ribosomal subunit mutated in susceptible strains and upregulated by UVR. Ribosome biogenesis was a major gene network upregulated in skin by UVR. Variation in the “usual suspect” mechanisms by which UVR may exacerbate melanoma, such as defective DNA repair, melanocyte proliferation, or inflammatory cell infiltration, did not explain melanoma susceptibility or resistance. Instead, events occurring soon after exposure, such as dysregulation of ribosome function, which can alter many aspects of cellular metabolism, may be important.