In the last few years the concept that ventricular remodelling produced by heart failure is irreversible has been challenged. Different strategies, including mechanical unloading, gene and cell therapy, at least in certain conditions, have shown to prevent or reverse myocardial remodelling and induce myocardial functional improvement. However, the mechanisms involved in this improvement are unknown. In particular, whether these new strategies induce myocardial functional recovery or regeneration with cardiomyogenesis remains to be established. Mechanical unloading using left ventricular assist devices (LVADs) has been associated with reverse remodelling in heart failure. Isolated cardiac myocytes from heart failure patients after LVAD treatment show functional improvement compared with myocytes isolated before the treatment (Terracciano et al., 2003). Excitation-contraction coupling in LVAD-treated myocytes is significantly improved, with a major role for sarcoplasmic reticulum calcium content (Terracciano et al., 2004), suggesting that functional cellular recovery can be responsible for the observed clinical improvement. New evidence suggests that formation of new cardiac myocytes may also occur during LVAD treatment, supporting the hypothesis of true myocardial regeneration in these patients (Wohlschlaeger et al., 2010). The understanding that an important mechanism of development of heart failure is the loss of cardiomyocytes leads to the notion of supplementing those losses by delivering cells directly into the diseased heart as a mode of treatment. During the last fifteen years there have been several studies performed in the field of cardiac cell transplantation involving a wide range of animal models and also in large clinical trials. Some of the reported data have stimulated much interest, and the field continues to be an active area of ongoing research. With this strategy cardiac functional improvement has been demonstrated but the mechanisms involved are debated. One study we have performed is the assessment of intracellular communication between adult progenitor cells and cardiac muscle cells. Using dual patch clamping we have found that it is possible to measure functional gap junction activity between different progenitor cells and cardiac myocytes in vitro, and that genetic manipulation of the progenitor cells can modulate such communication, representing a useful strategy for improving integration of the transplanted cells in the host myocardium (Stagg et al., 2006). In another study we have investigated the in vivo and in vitro effects of bone marrow mononuclear cells or skeletal myoblasts on the function of neighbouring cardiomyocytes in a rat model of heart failure. Four weeks after injection both cell types improved ejection fraction; isolated ventricular myocytes, however, were all of recipient origin. Our data confirmed previous observations that bone marrow mononuclear cells or skeletal myoblasts do not transdifferentiate into cardiomyocytes in a sufficient number to induce myocardial regeneration, and suggested that more adequate cell types should be used in this approach. Another observation from this study is that functional parameters of recipient cardiac cells are improved after cell injection, suggesting that cell therapy has important effects on the host myocardium(Lee et al., 2009). Paracrine mechanisms may account for the observed changes in heart function. Using a co-culture system, we have shown that adult progenitor cells influence contractility and calcium handling in neighbouring failing cardiomyocytes by soluble mediators, supporting the paracrine hypothesis. Our studies suggest that recovery of the existing myocardium should be considered when evaluating the efficacy of stem cell therapy(Lee et al., 2008). Further characterization of the pathophysiology of heart failure and elucidation of the physiological mechanisms responsible for the beneficial effects mediated by transplanted cells under specific disease states would hold the best promise towards optimizing the future results. More research is needed to assess the value of promising new cell types, such as cardiac progenitor cells or induced pluripotent stem cells, in their ability to differentiate in cardiac tissue and to dissect the role of the host environment in the integration and differentiation of the transplanted cells.