In this paper, we review information regarding the status of the native fishes of the combined Sacramento River and San Joaquin River drainages (hereinafter the "Sacramento-San Joaquin drainage") and the factors associated with their declines. The Sacramento-San Joaquin drainage is the center of fish evolution in California, giving rise to 17 endemic species of a total native fish fauna of 28 species. Rapid changes in land use and water use beginning with the Gold Rush in the 1850s and continuing to the present have resulted in the extinction, extirpation, and reduction in range and abundance of the native fishes. Multiple factors are associated with the declines of native fishes, including habitat alteration and loss, water storage and diversion, flow alteration, water quality, and invasions of alien species. Although native fishes can be quite tolerant of stressful physical conditions, in some rivers of the drainage the physical habitat has been altered to the extent that it is now more suited for alien species. This interaction of environmental changes and invasions of alien species makes it difficult to predict the benefits of restoration efforts to native fishes. Possible effects of climate change on California's aquatic habitats add additional complexity to restoration of native fishes. Unless protection and restoration of native fishes is explicitly considered in future water management decisions, declines are likely to continue.