The Frank–Starling Law dictates that the heart is able to match ejection to the dynamic changes occurring during cardiac filling, hence efficiently regulating isovolumetric contraction and shortening. In the last four decades, efforts have been made to identify a common fundamental basis for the Frank–Starling heart that can explain the direct relationship between muscle lengthening and its increased sensitization to Ca2+. The term ‘myofilament length-dependent activation’ describes the length-dependent properties of the myofilaments, but what is(are) the underlying molecular mechanism(s) is a matter of ongoing debate. Length-dependent activation increases formation of thick-filament strongly-bound cross-bridges on actin and imposes structural–mechanical alterations on the thin-filament with greater than normal bound Ca2+. Stretch-induced effects, rather than changes in filament spacing, appear to be primarily involved in the regulation of length-dependent activation. Here, evidence is provided to support the notion that stretch-mediated effects induced by titin govern alterations of thick-filament force-producing cross-bridges and thin-filament Ca2+-cooperative responses.