Sp1, a triple C2H2 zinc finger protein, has been studied for more than two decades and biochemical features of the protein have been well documented. However, its biological roles in humans are still ambiguous. Recent studies on Huntington’s disease have shown that the mutant huntingtin proteins with expanded polyglutamine tracts interact with transcription factors, such as TFIID and Sp1, and have provided new insights into mechanisms of gene transcription as well as Huntington’s disease. Here, I describe aspects of Sp1 function in the context of Huntington’s disease research.