The Kruppel-like factor (KLF) family of transcription factors regulates diverse cell biological processes including proliferation, differentiation, survival and growth. Previous studies have shown that KLF15 inhibits cardiac hypertrophy by repressing the activity of pivotal cardiac transcription factors such as GATA4, MEF2 and myocardin. We set out this study to characterize the interaction of KLF15 with putative other transcription factors. We first show that KLF15 interacts with myocardin-related transcription factors (MRTFs) and strongly represses the transcriptional activity of MRTF-A and MRTF-B. Second, we identified a region within the C-terminal zinc fingers of KLF15 that contains the nuclear localization signal. Third, we investigated whether overexpression of KLF15 in the heart would have therapeutic potential. Using recombinant adeno-associated viruses (rAAV) we have overexpressed KLF15 specifically in the mouse heart and provide the first evidence that elevation of cardiac KLF15 levels prevents the development of cardiac hypertrophy in a model of Angiotensin II induced hypertrophy.