Since the seminal paper by Orlic and colleagues in 2001, which demonstrated that local injection of bone marrow-derived stem cells leads to an improvement in cardiac function in a mouse model of myocardial infarction (MI; Orlic et al., 2001), there has been considerable debate with regard to the mechanism by which cardiac repair is achieved. The results in the original paper suggested that the bone marrow-derived allogeneic cells underwent transdifferentiation into cardiomyocytes, thereby repairing the infarcted myocardium. Since then, other groups have shown that bone marrow-derived cells can affect cardiac repair, but no formation of new cardiomyocytes has been observed (Murry et al., 2004; Nygren et al., 2004; Balsam and Robbins, 2005). In order to reconcile these observations, several hypotheses have been proposed to explain cardiac repair in the absence of regeneration and are summarized in Figure 1 (Lovell and Mathur, 2010). Although all of the proposed mechanisms are based on associated evidence, the ‘paracrine effect’ appears to have the most data supporting it, irrespective of the cell type used (Kinnaird et al., 2004; Gnecchi et al., 2005; Xu et al., 2007; Korf-Klingebiel et al., 2008; Ratajczak et al., 2012). The paracrine effect proposes that cells delivered to the site of organ injury (in this case MI) secrete a factor or a combination of factors that have a beneficial effect on cardiac function that is achieved either by enhancing surviving myocyte function, by preventing cell loss as a result of the ischaemic insult (e.g. activation of survival pathways) or stimulating ‘resident’ stem cell niches. The potential identification of individual factors as part of this hypothesis immediately raises the possibility of understanding the ligand–receptor interaction and hence the development of new pharmacological targets in the field of regenerative medicine. The development of an off-the-shelf drug that is capable of myocardial repair and can easily be applied to ‘all comers’ has clinical appeal and would revolutionize the application of regenerative medicine. Although considerable obstacles need to be overcome, more evidence is accumulating to bring the field closer to understanding whether the mechanisms of cell-derived therapy can be dissected down to the ‘basic pharmacology’ that controls them. The role that pharmacology plays as an adjunct to current approaches to cell therapy should also not be overlooked and demonstrates a significant partnership between the two fields. Below, this partnership will be explored using the clinical trials that have targeted cardiovascular disease as an example. Factors that have been identified as part of the paracrine hypothesis will be discussed and the potential for the development of a purely pharmacological approach considered. Figure 1 Potential mechanisms of stem cell therapy. Although initial research was focused on whether stem cells transdifferentiate into functioning cardiomyocytes, subsequent research has supported the existence of other mechanisms including the paracrine hypothesis. ...