Different cell types, equipped with unique structure and function, synthesize different sets of proteins on the basis of different patterns of gene expression, even though their genomes are identical. Cardiac transcription factors have been reported to control a cardiac gene program and thus to play a crucial role in transcriptional regulation during embryogenesis. Recently, postnatal roles of cardiac transcription factors have been extensively investigated. Consistent with the direct transactivation of numerous cardiac genes reactivated in response to hypertrophic stimulation, cardiac transcription factors are profoundly involved in the generation of cardiac hypertrophy or in cardioprotection from cytotoxic stress in the adult heart. In this review, the regulation of a cardiac gene program by cardiac transcription factors is summarized, with an emphasis on their potential role in the generation of cardiac hypertrophy.