Abstract: Autophagy is an essential process for the maintenance of cellular homeostasis in the heart under both normal and stress conditions. Autophagy is a key degradation pathway and acts as a quality control sensor. It protects myocytes from cytotoxic protein aggregates and dysfunctional organelles by quickly clearing them from the cell. It also responds to changes in energy demand and mechanical stressors to maintain contractile function. The autophagic–lysosomal pathway responds to serum starvation to ensure that the cell maintains its metabolism and energy levels when nutrients run low. In contrast, excessive activation of autophagy is detrimental to cells and contributes to the development of pathological conditions. A number of signaling pathways and proteins regulate autophagy. These include the 5′-AMP-activated protein kinase/mammalian target of rapamycin pathway, FoxO transcription factors, Sirtuin 1, oxidative stress, Bcl-2 family proteins, and the E3 ubiquitin ligase Parkin. In this review, we will discuss how this diverse cast of characters regulates the important autophagic process in the myocardium.