Selective estrogen receptor modulators (SERMs) are tissue- and context-specific regulators of estrogen receptor (ER) signaling, originally developed to treat breast cancer and osteoporosis. Increasing recognition of the roles of ERα and ERβ in modulation of immune cell development, tolerance, inflammation and antiviral defense has led to growing interest in SERMs as potential therapies for autoimmune disease. This review summarizes current mechanistic, preclinical, and clinical evidence on SERMs and related ER-directed agents across autoimmune and immune-mediated conditions. Preclinical studies demonstrated that select SERMs can generate anti-inflammatory or tissue-protective effects of endogenous estrogen without negatively impacting reproductive tissue. In inflammatory arthritis, SERMs reduced synovial inflammation, modulated Th17-associated responses, and protected against bone loss in murine models. In systemic lupus erythematosus (SLE), where estrogen signaling contributes to disease susceptibility and activity, SERMs and SERDs showed variable but encouraging findings: raloxifene improved bone mineral density without increasing lupus flares, bazedoxifene preserved trabecular bone in lupus-prone mice, and fulvestrant reduced disease activity and T-cell activation markers in a randomized trial. In multiple sclerosis, ERα-dependent mechanisms mediate estradiol’s protective effects in experimental autoimmune encephalomyelitis (EAE), illustrating the broader immunologic relevance of estrogen pathways. Given the high burden of glucocorticoid exposure, premature ovarian insufficiency, and osteoporosis among individuals with autoimmune diseases, SERMs may offer dual benefit as both immunomodulatory and bone-protective agents. However, available human studies remain small and short-term. Future work should define cell-specific ER signaling in human immunity and autoimmunity, identify patient subgroups most likely to benefit, and evaluate long-term safety in adequately powered clinical trials.