Calcium is integral to cardiac excitation and contraction. The main route for calcium influx into cardiac myocytes is the L-type Ca2+ channel. Once intracellular calcium levels are increased, a number of calcium-dependent signal pathways are activated that can lead to persistent changes in protein synthesis and function. This process is termed “pathological remodeling”. Pathological remodeling of the heart can progress to irreversible changes in heart size and function that ultimately results in heart failure and death. It is well recognized that calcium-dependent pathways contribute to the process of pathological remodeling but reactive oxygen species have also emerged as an important participant in cardiac pathology. The early mechanisms that trigger remodeling have been poorly understood. Recent evidence links calcium influx through the L-type Ca2+ channel with persistent changes in cellular calcium and cellular redox state as a possible early mediator of pathological remodeling.