Hematopoietic progenitor and stem cells (HPSCs) have been employed in cell-based therapy (CBT) to promote neovascularisation and regeneration of ischemic organs, such as heart and limbs. Furthermore, endothelial progenitor cells (EPCs) may favour tumour growth and adverse vascular targeting treatment by incorporating into neovessels. CBT is hampered by the paucity of HPSCs harvested from peripheral blood and suffers from several pitfalls, including the differentiation outcome of transplanted cells and low percentage of engrafted cells. Therefore, CBT will benefit of a better understanding of the signal transduction pathway(s) which drive(s) HPSC homing, proliferation and incorporation into injured tissues. At the same time, this information might outline alternative molecular targets to combat tumoral neovascularisation. The elevation in intracellular Ca 2+ concentration is the key signal in the regulation of cellular motility, replication, and differentiation. Intracellular Ca 2+ waves regulate cytoskeleton re-organisation and disassembly at focal adhesions, thus stimulating migration and substrate adhesion, and induce DNA transcription by recruiting Ca 2+-sensitive transcription factors. However, the Ca 2+ signalling toolkit which underlies Ca 2+ release from intracellular stores and Ca 2+ entry across the plasmalemma in HPSCs is still unclear. Our recent work has shown that the so-called store-operated Ca 2+ entry stimulates EPC growth. Unravelling the mechanisms guiding HPSC behaviour might supply the biological bases required to improve CBT. For instance, genetic manipulation of the Ca 2+ signalling machinery (such as transfer of genes encoding for the Ca 2+ channels involved in EPC proliferation) could provide a novel approach to increase the extent of limb neovascularisation and regeneration of damaged hearts.