Abstract The naked mole-rat (Bathyergidae; Heterocephalus glaber ) is an extremophilic rodent that lives an extraordinarily long and healthy life despite having evolved in harsh, arid, underground conditions. This ~ 31-million-year evolutionary path and concomitant adaptations have surprisingly yielded a broad suite of cytoprotective mechanisms that have enabled them to avoid cancer. Compared to above-ground dwelling species, the incidence of spontaneous neoplasia in naked mole-rats is extremely low. Naked mole-rats also evade experimental induction of tumorigenesis by both chemical carcinogens and physical stressors, even though their cells can be transformed with high levels of oncogene exposure or transduced with additional oncogenes. While the exact blueprint that the naked mole-rat has evolved to provide this profound resistance to cancer remains elusive, it is clear that multiple genomic and molecular mechanisms are involved. These involve both cell autonomous and non-autonomous mechanisms and include a more cytoprotective intracellular environment, efficient DNA repair processes, a low abundance of tumor-promoting oncogenes, unique adaptations in several signaling pathways (e.g., Wnt pathways), greater reliance on highly responsive innate immune cells, dampened inflammatory responses to carcinogenic insults, an abundance of stable tumor suppressor genes (e.g., p53), and unique (e.g., INK4a mediated) cell death mechanisms. A circulating population of cytotoxic γδT cells provides an additional layer of protection against cancer development, progression and metastasis. A subset of these multifaceted mechanisms is shared with the muroid, subterranean-dwelling, cancer-resistant, Middle Eastern blind mole-rat (Nannospalax ehrenbergi ), suggesting that phylogenetically independent, convergent, evolutionary tinkering has contributed to their common cancer-resistant phenotype. Elucidating these multi-layered, disparate evolved mechanisms will provide valuable, translational insights into the critical components and protections of this devastating disease and may hopefully lead to novel therapeutics.