Adult male germ cell tumors (GCTs) arise by transformation of totipotent germ cells. They have the unique potential to activate molecular pathways, in part mimicking those occurring during gametogenesis and normal human development, as evidenced by the array of histopathologies observed in vivo. Recent expression profiling studies of GCTs along with advances in embryonic stem-cell research have contributed to our understanding of the underlying biology of the disease. Gain of the short arm of chromosome 12 detected in almost all adult GCTs appears to be multifunctional in germ cell tumorigenesis on the basis of the observed overexpression of genes mapped to this region involved in maintenance of pluripotency and oncogenesis. Expression signatures associated with the different histopathologies have yielded clues as to the functional mechanisms involved in GCT invasion, loss of pluripotency, and lineage differentiation. Genomic and epigenomic abnormalities that contribute to or cause these events have been identified by traditional genome analyses and continue to be revealed as genome-scanning technologies develop. Given the high sensitivity of most GCTs to cisplatin-based treatment, these tumors serve as an excellent model system for the identification of factors associated with drug resistance, including differentiation status and acquisition of genomic alterations. Overall, adult male GCTs provide a unique opportunity for the examination of functional links between transformation and pluripotency, genomic and epigenomic abnormalities and lineage differentiation, and the identification of genetic features associated with chemotherapy resistance.