Two main hemodynamic overload mechanisms [i.e., volume and pressure overload (VO and PO, respectively] result in heart failure (HF), and these two mechanisms have divergent pathologic alterations and different pathophysiological mechanisms. Extensive evidence from animal models and human studies of PO demonstrate a clear association with alterations in Ca²⁺ homeostasis. By contrast, emerging evidence from animal models and patients with regurgitant valve disease and dilated cardiomyopathy point toward a more prominent role of myofilament dysfunction. With respect to VO HF, key features of excitation–contraction coupling defects, myofilament dysfunction, and extracellular matrix composition will be discussed.