Despite our deepening understanding of the mechanisms of resistance and intensive efforts to develop therapeutic solutions to combat resistance, de novo and acquired tamoxifen resistance remains a clinical challenge, and few effective regimens exist to treat tamoxifen-resistant breast cancer. The complexity of tamoxifen resistance calls for diverse therapeutic approaches. This review presents several therapeutic strategies and lead compounds targeting the estrogen receptor signaling pathways for treatment of tamoxifen-resistant breast cancer, with a critical assessment of challenges and potentials regarding clinical outcome. Medicinal chemistry holds the key to effective, personalized combination therapy for tamoxifen-resistant breast cancer by making available a diverse arsenal of small-molecule drugs that specifically target signaling pathways modulating hormone resistance. These combination therapy candidates should have the desired specificity, selectivity and low toxicity to resensitize tumor response to tamoxifen and/or inhibit the growth and proliferation of resistant breast cancer cells.