A number of placenta-specific genes (e.g., Tpbp, Plac1, Syncytin, and retrotransposon-associated genes such as Peg10, Rtl1, Endothelin B receptor, Insl4, Leptin, Midline1, and Pleiotrophin), enhancer elements (e.g., glycoprotein hormone alpha-subunit) and gene isoforms (e.g., 3betaHSD, Cyp19), as well as placenta-specific members of gene families (e.g., Gcm1, Mash2, Rhox, Esx1, Cathepsin, PAG, TKDP, Psg, Siglec) have been identified. This review summarizes their evolution, regulation, and biochemical functions and discusses their significance for placental development and function. Strikingly, the number of unique, truly placenta-specific genes that have been discovered to date is very small. The vast majority of placenta-specific gene products have resulted from one of three mechanisms: evolution of placenta-specific promoters, evolution of large gene families with several placenta-specific members, or adoption of functions associated with endogenous retroviruses and retroelements. Interestingly, nearly all the examples of placenta-specific genes that have been discovered to date are not present in all placental mammals.