Huntington's disease (HD) is an autosomal dominant condition, resulting from a mutation in huntingtin (htt). Htt is a novel protein, and its normal function is at present not well understood. Nuclear translocation of mutant htt in vitro up-regulates expression of the cell death gene caspase-1. We have demonstrated in a transgenic HD mouse model that caspase-1 and caspase-3 are transcriptionally up-regulated and activated. Underscoring the relevancy of these findings, recent results suggest that caspase-1 is activated in brains of humans with HD. Caspase activation results in the proteolytic cleavage of key cellular targets, including htt, leading to cell dysfunction. Caspase activation leading to cell dysfunction and death correlates with disease progression. In HD-transgenic mice, caspase inhibition resulted in a delayed onset of symptoms, a slowed progression, and prolonged survival. Caspase inhibition is a therapeutic strategy that merits evaluation in humans with HD.