Many estuarine ecosystems and the fish communities that inhabit them have undergone substantial changes in the past several decades, largely due to multiple interacting stressors that are often of anthropogenic origin. Few are more impactful than droughts, which are predicted to increase in both frequency and severity with climate change. In this study, we examined over five decades of fish monitoring data from the San Francisco Estuary, California, U.S.A, to evaluate the resistance and resilience of fish communities to disturbance from prolonged drought events. High resistance was defined by the lack of decline in species occurrence from a wet to a subsequent drought period, while high resilience was defined by the increase in species occurrence from a drought to a subsequent wet period. We found some unifying themes connecting the multiple drought events over the fifty-year period. Pelagic fishes consistently declined during droughts (low resistance), but exhibit a considerable amount of resiliency and often rebound in the subsequent wet years. However, full recovery does not occur in all wet years following droughts, leading to permanently lower baseline numbers for some pelagic fishes over time. In contrast, littoral fishes seem to be more resistant to drought and may even increase in occurrence during dry years. Based on the consistent detrimental effects of drought on pelagic fishes within the San Francisco Estuary and the inability of these fish populations to recover in some years, we conclude that freshwater flow remains a crucial but not sufficient management tool for the conservation of estuarine biodiversity.