The salt marsh harvest mouse (SMHM, Reithrodontomys raviventris) is an endangered species, endemic to the San Francisco Estuary. Despite being protected for almost half a century and being included in a large number of recovery, restoration, and management plans, significant data gaps hinder conservation and management of the species, a challenge further complicated by developing threats such as climate change. In this review, we present the current state of knowledge; highlight research gaps on habitat requirements and distribution, taxonomic status and genetic structure, physiology, reproduction and demographics, population dynamics, and behavior and community interactions; and present an overview of threats to the species. Our review indicates that substantial data gaps exist; although some aspects of SMHM ecology, such as habitat use, have been addressed extensively, others, such as the effects of environmental contamination, are largely unaddressed. We suggest that conservation and restoration-planning processes consider experimental approaches within restoration designs to address these deficiencies. Continued investment in basic and applied SMHM ecology to collect baseline and long-term data will also be beneficial. Additionally, further coordination among managers and researchers can facilitate more effective responses to uncertainties and emerging threats, especially climate change, which threatens the SMHM and its habitat throughout its range.