The phenomenon of intracellular Ca²⁺ wave propagation can be interpreted as reaction-diffusion waves driven by Ca²⁺-induced Ca²⁺ release (CICR). However, in cardiac cells, the low Ca²⁺ sensitivity of the sarcoplasmic Ca²⁺-release channels (about 100 mM for RyR2) is difficult to reconcile with the observation that a Ca²⁺ wave-front rarely exceeds a few hundred nM [Ca²⁺]. Recently, a prominent role for intra-store Ca²⁺ in sensitization of RyRs and in CICR termination during SR Ca²⁺ release has been suggested. Thus, Ca²⁺ waves could be driven by local RyR sensitization mediated by SR loading via the SR Ca²⁺ pump (SERCA). This region at the Ca²⁺ wave-front would skip in a saltatoric fashion from sarcomere to sarcomere inside the SR. In this study, UV-flash photolytic release of a SERCA inhibitor from the new caged compound Nmoc-DBHQ induced an instantaneous slowing of Ca²⁺ wave propagation in cardiac muscle cells, as examined by laser-scanning confocal Ca²⁺ imaging (from 95.8±5.9 mm/s in control to 69.3±1.8 mm/s after the flash). This finding is contrary to predictions derived from the classical view of Ca²⁺ wave propagation by CICR, but consistent with the concept that SR Ca²⁺ loading via SERCA leads to sensitization of RyRs, thereby creating a traveling wave of high Ca²⁺ sensitivity. Thus, in cardiac muscle, Ca²⁺ wave propagation appears to be driven by a traveling wavefront of CICR sensitization rather than by CICR itself.