Transient receptor potential (TRP) channels of multiple subclasses are expressed in the heart, although their functions are only now beginning to emerge, especially for the TRPC subclass that appears to regulate the cardiac hypertrophic response. Although TRP channels permeate many different cations, they are most often ascribed a specific biological function because of Ca²⁺ influx, either for microdomain signaling or to reload internal Ca²⁺ stores in the endoplasmic reticulum through a store-operated mechanism. However, adult cardiac myocytes arguably do not require store-operated Ca²⁺ entry to regulate sarcoplasmic reticulum Ca²⁺ levels and excitation–contraction coupling; hence, TRP channels expressed in the heart most likely coordinate signaling within local domains or through direct interaction with Ca²⁺-dependent regulatory proteins. Here, we review the emerging evidence that TRP channels, especially TRPCs, are critical regulators of microdomain signaling in the heart to control pathological hypertrophy in coordination with signaling through effectors such as calcineurin and NFAT (nuclear factor of activated T cells).