Endothelial progenitor cells (EPCs) are a heterogeneous cluster of cells which have received a growing interest since the seminal work by Asahara et al., in 1997. These cells are born in the bone marrow and are released to the blood in response to ischemia; they subsequently attach to damaged vessels and repopulate the endothelium or support local angiogenesis. Unfortunately, there is not a consensus definition of “EPC” based on surface markers or proliferate capabilities; however, most studies so far have assessed these cells by flow cytometry as CD34+/KDR+ events, although many cells included under this definition behave as angiogenic monocytes. Nevertheless, EPCs and angiogenic cells seem to work together in order to maintain a healthy endothelial function. EPCs and angiogenic monocytes are originated from the bone marrow and guided by their chemokine receptor CXCR-4, which binds to ischemic-related SDF-1. In this journey, these cells subsequently acquire CD34, CD133, KDR, CD144 or VE-cadherin and von Willebrand factor. After reaching their destination, these cells secrete angiogenic factors to support local endothelial cells. This paracrine angiogenic role seems to be the key effect of these cells, according to the recent experimental data. This paracrine function is able to promote endothelial cell survival and subsequent maintenance of vascular tone, haemostasis and lack of inflammation. Thus, a healthy vascular function is repaired or maintained. Of note, a healthy vascular function has been demonstrated to be deeply and early disrupted in atherosclerosis, the first global cause of death. Atherosclerotic vascular disease is able to decrease the number and function of EPCs. This decrease is directly linked to coronary obstruction beyond classical cardiovascular risk factors. In the last years it has been becoming increasingly evident that EPCs are initially increased after vascular damage, being further depleted in advanced cardiovascular disease. Many research efforts are being made in order to elucidate which factors determine an abnormal release of EPCs from their bone marrow origin and mediate this EPC exhaustion in atherosclerosis. It is expected that bone marrow will become the last frontier for our understanding of EPC dysfunction in atherosclerosis, and may set the basis for a putative unification of the vasculogenic and immune hypotheses of atherosclerosis. EPCs and related cells are easily measured from peripheral blood by flow cytometry. Further clinical EPC assessments under a common protocol will set the basis for their usage as a sensitive and specific diagnostic and prognostic marker, since a single cell may be understood as the result of thousands of molecular interactions. EPCs may also be used as a therapeutic agent. Clinical trials show a promising value in terms of ejection fraction and survival, although the elucidation of the best EPC population and technical procedure will still take several years of effort. Eventually, classical cardiovascular drugs (eg. statins, pioglitazone) and target-designed ones are able to stimulate EPC function. This goal may also be achieved by target engineered scaffolds for cardiovascular surgery and endovascular stents.