The Kruppel-like Factor (KLF) family of zinc-finger transcription factors are critical regulators of cell differentiation, phenotypic modulation and physiologic function. An emerging body of evidence implicates an important role for these factors in cardiovascular biology, however, the role of KLFs in muscle biology is only beginning to be understood. This article reviews the published data describing the role of KLFs in the heart, smooth muscle, and skeletal muscle and highlights the importance of these factors in cardiovascular development, physiology and disease pathobiology.