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The estrogen receptor (ER) is a potentially useful biological target for diagnosis and therapy in hormonally responsive human breast cancer. This protein is often overexpressed both on the membrane and on the nuclear compartment of breast cancer cells and therefore provides a mechanism for targeted drug delivery. Over the past 30 years, many research groups have attempted to exploit the high affinity and receptor selectivity of steroidal estrogens to deliver cytotoxic agents that by themselves lack selectivity. In this review, we describe the strategies and methods employed by those investigators in their efforts to develop steroid-drug conjugates with the goals of enhanced antiproliferative activity and ER-selectivity. In particular, the choices of steroid scaffolds and sites for drug conjugation have evolved as the understanding of role of ER in cell function has expanded. Present knowledge of the mechanism of action for estrogens and antiestrogens helps explain the failure of most efforts to achieve their stated objectives. The review culminates in the description of our program, which has produced the first conjugate that clearly has achieved those goals and provides an approach for developing new agents for future clinical use.