Members of the metazoan nuclear receptor superfamily regulate gene expression programs in response to binding of cognate lipophilic ligands. Evolutionary studies using bioinformatics tools have concluded that lower eukaryotes, such as fungi, lack nuclear receptor homologs. Here we review recent discoveries suggesting that members of the fungal zinc cluster family of transcription regulators represent functional analogs of metazoan nuclear receptors. These findings indicate that nuclear receptor-like ligand-dependent gene regulatory mechanisms emerged early during eukaryotic evolution, and provide the impetus for further detailed studies of the possible evolutionary and mechanistic relationships of fungal zinc cluster transcription factors and metazoan nuclear receptors. Clinical implications of the discovery of nuclear receptor-like transcription factors in pathogenic fungi will also be discussed.