Phospholipase C (PLC) is considered to mediate the cardiomyocyte hypertrophic response to norepinephrine. However, a paucity of information exists regarding the regulation of specific PLC isozyme gene and protein expression as well as activities in normal and hypertrophied myocardium. In this chapter, the role of PLC isozymes in cardiac hypertrophy as well as some of the mechanisms that are involved in the regulation of PLC isozyme gene expression, protein abundance and activities are discussed. On the basis of the available literature, it is suggested that specific PLC isozymes could be involved in the cardiomyocyte response to different hypertrophic stimuli and that modification of the transcriptional regulation of PLC isozymes could also prevent the progression of cardiac hypertrophy and its transition to heart failure.