Thiazolidinediones (TZDs) are an exciting new class of insulin-sensitizing drugs being used currently for the treatment of non-insulin-dependent diabetes mellitus. The molecular target of these compounds is thought to be the nuclear hormone receptor, peroxisome proliferator-activated receptor gamma (PPARgamma). PPARgamma is expressed predominantly in adipose tissue, yet a major site of TZD-responsive glucose disposal is skeletal muscle. Potential explanations for this paradox are discussed in this review.