The nuclear receptor (NR) superfamily is a diverse group of over 50 proteins whose function is to regulate the transcription of a vast array of cellular genes. These proteins are able to tune transcription over an extremely dynamic range due to the fact that they may act as either transcriptional activators or repressors depending on promoter context and ligand status. Due to these unique properties, diverse families of viruses have evolved strategies to exploit NRs in order to regulate expression of their own genes and to optimize the cellular milieu to facilitate the viral lifecycle. While the specific NRs targeted by these viruses vary, the strategies used to target them are common. This is accomplished at the cis-level by incorporation of nuclear receptor response elements into the viral genome and at the trans-level by viral proteins that target NRs directly or indirectly to modulate their function. The specific NR(s) targeted by a particular virus are likely to be reflective of the tissue tropism of the virus in question. Thus, the essential role played by NRs in the replication cycles of such diverse viruses underscores the importance of understanding their functions in the context of specific infections. This knowledge will allow appropriate considerations to be made when treating infected individuals with hormone-associated diseases and will potentially assist in the rational design of novel antiviral therapeutics.