Mechanical stress is a major triggering stimulus for the installation of cardiac hypertrophy as well as for the structural and functional deterioration occurring in the hypertrophy decompensation. The sensing of mechanical forces and their conversion into biochemical signals depend on the integrity of subcellular structures such as the costameres and Z-disks. Signaling molecules concentrated into these structures are thought to be activated by the stress-induced deformation of structural proteins. Evidence also indicates that Ca2+ may be involved in mediating the mechanical forces conversion into biochemical signals and biological responses. Ca2+ channels, transporters and activated proteins are concentrated at the junctions between the T-tubules and the sarcoplasmic reticulum which are in close proximity to the costameres and Z-disks. This provides a structural basis for the influence of mechanical forces on Ca2+ transport and on the events related to signaling molecules clustered in the costameres and the Z-disks. Emerging data reviewed here are providing insight into how Ca2+ and mechanical mediated signaling are coordinated to modulate the functional and trophic responses of cardiac myocytes to mechanical stress.