The family of nuclear hormone receptors continues to be a rich source of drug discovery targets. In addition to traditional structure-based design methods for receptor-ligand design, the nuclear hormone receptor family presents an additional challenge. The receptor-ligand complex can adopt a conformation that attracts a family of co-activators and co-repressor proteins leading to very specific biological profiles. Several specific receptor modulators have been discovered that exhibit novel biological properties that have either entered the clinic or are in the advanced stages of preclinical research. Some examples will be presented to highlight how this exciting area has emerged over the past decade while projecting some future trends. The focus of this chapter will not be a comprehensive summary of the many examples in the last decade since several reviews are available . Rather, this chapter will highlight some of the strategies and challenges facing the design of specific ligands using X-ray and molecular modeling methods.