Germ cells are highly specialized cells that form gametes (sperm and eggs), and they are the only cells within an organism that contribute genes to offspring. Due to the fact that the genetic information contained within germ cells is passed from generation to generation, the germ line is often thought of as immortal. Studies have revealed that germ cells are remarkably similar to pluripotent embryonic stem cells (ESCs). For example, there is a significant overlap in the gene expression profile between ESCs and primordial germ cells (PGCs), the founders of the germ cell lineage. In addition, pluripotent embryonic germ (EG) cell lines have been derived from mammalian PGCs. Secondly, a subset of testicular germ cell tumors, known as non-seminomas, often contain differentiated cells representative of all three germ layers, a definitive test of pluripotency. Lastly, recent results have demonstrated the ability of spermatogonial stem cells (SSCs) to de-differentiate into pluripotent ES-like cells, underscoring a unique relationship between the germ line and pluripotent cells that are present during the earliest stages of embryonic development. Here, we will review the factors that regulate the self-renewal and maintenance of male germline stem cells (GSCs) and discuss how these factors may allow us to manipulate the germ line to create pluripotent cells that could serve as a critical tool in cell replacement therapies and regenerative medicine.