Members of the tripartite motif (TRIM) protein family are found in all multicellular eukaryotes and function in a wide range of cellular processes such as cell cycle regulation, differentiation, development, oncogenesis and viral response. Over the past few years, several TRIM proteins have been reported to control gene expression through regulation of the transcriptional activity of numerous sequence-specific transcription factors. These proteins include the transcriptional intermediary factor 1 (TIF1) regulators, the promyelocytic leukemia tumor suppressor PML and the RET finger protein (RFP). In this chapter, we will consider the molecular interactions made by these TRIM proteins and will attempt to clarify some of the molecular mechanisms underlying their regulatory effect on transcription.