This review focuses on recent developments in the molecular mechanisms by which Ca activates cardiac sarcomeres and how these mechanisms play out in the cardiac cycle. I emphasize the role of mechanisms intrinsic to the sarcomeres as significant determinants of systolic elastance and ventricular stiffening during ejection. Data are presented supporting the idea that processes intrinsic to the thin filaments may promote cooperative activation of the sarcomeres and be an important factor in maintaining and modifying systolic elastance. Application of these ideas to translational medicine and rationale drug design forms an important rationale for detailed understanding of these processes.