Despite several improvements in term of diagnosis and prevention, ischemic heart disease still represents one of the principal worldwide causes of death. Cardiac progenitor cells (CPCs) based therapy is considered a valid alternative to heart transplant, but several issues concerning the transplanted cells viability, retention and therapeutic effect need to be solved. Tissue engineering, mixing synthetic or natural polymers with injected cells, could represent the way through which overcomes shortages and set up an effective cardiac regenerative therapy. Nowadays, it is well known that cardiac extracellular matrix (ECM) provides structural and functional integrity, affects cardiac function, development and physiologic repair. In this optic, ECM and ECM-like materials represent functional and biocompatible tools with a great potential to serve as natural or nature-mimicking scaffolds in the field of regenerative medicine. The aim of the present work is to provide an overview on the state of the art and recent advantages on CPCs and scaffold-based therapy for heart regeneration.