Steroid hormone receptors belong to the nuclear receptor superfamily of ligand-dependent transcription factors and are the main effectors of steroid hormone action. A number of marketed drugs currently used in the management of multiple disorders target steroid receptors, reflecting their broad homeostatic function and therapeutic potential. The discovery and development of selective estrogen receptor modulators (SERMs), such as tamoxifen and raloxifene, that mimic the natural hormone in certain tissues but antagonize it in others, led to a new approach to exploit and expand the therapeutic utility of synthetic steroid receptor ligands. Indeed, recent work suggests that the 'SERM' or 'selective nuclear receptor modulator' concept can be expanded to other members of the nuclear receptor family. Here, the authors discuss opportunities and challenges in the development of novel therapeutic agents targeting members of the steroid hormone receptors.