Cloned 20 years ago, stem cell antigen-1 (Sca-1) is used extensively to enrich for murine hematopoietic stem cells. The realization that many different stem cell types share conserved biochemical pathways has led to a flood of recent research using Sca-1 as a candidate marker in the search for tissue-resident and cancer stem cells. Although surprisingly little is still known about its biochemical function, the generation and analysis of knockout mice has begun to shed light on the functions of Sca-1 in stem and progenitor cells, demonstrating that it is more than a convenient marker for stem cell biologists. This review summarizes the plethora of recent findings utilizing Sca-1 as a parenchymal stem cell marker and detailing its functional role in stem and progenitor cells and also attempts to explain the lingering mysteries surrounding its biochemical function and human ortholog. Disclosure of potential conflicts of interest is found at the end of this article.