Osteoarthritis (OA) is a leading cause of chronic pain and disability, not only in the United States but also worldwide. The burden of OA is higher in women than in men. Estrogen as a possible explanation for observed sex differences in OA has not been definitively established. The purpose of this review was to summarize the results from studies of estrogen, estrogen depletion and treatment, and their impact on knee, hip, hand, and spine OA. We conducted a targeted review of the literature using PubMed. Although several studies show that hormone replacement therapy has the potential to be protective of OA for some joints, there are studies that showed no protective effect or even adverse effect. Taken together, the evidence for the protective effect of estrogen therapy depends on OA joint, OA outcome, and study design. Although this area has been studied for decades, more exclusively since the 1990s, there is a lack of high-quality experimental research in this topic. The lack of definitive conclusion on whether estrogen can play a role in the development in OA of either the knee, hip, spine, or hand is often in part due to the noncomparability of studies existing within the literature. Differences in diagnostic criteria, imaging modalities, populations studied, study designs, and outcome measures, as well as random error, have all contributed to inconclusive evidence. Future research on the role of estrogen in OA is needed, particularly as global demographic shifts in increasing overweight/obesity prevalence and ageing populations may contribute to widening OA-related health inequalities.