Nuclear receptor ligands regulate diverse developmental and physiological processes by activating intracellular members of the nuclear receptor superfamily. Activated nuclear receptors mediate the expression of distinct gene networks in vivo by an as yet unspecified mechanism. Central to the process is the recruitment by these receptors of coactivators, a functionally diversified set of factors shown to be required for efficient transcriptional regulation by activated receptors. This article will highlight recent advances in selected mechanistic aspects of receptor function, as well as discussing the potential of coactivators to act as mediators of the intricate pharmacology of nuclear receptor ligands.