Tumoral angiogenesis is mainly an endothelial cell-mediated process, which has been largely demonstrated to take on a crucial role in tumor growth, invasion, and metastasis. Thus, tumor-associated neovasculature represents a pivotal target in cancer therapy. Several mechanisms take part in the genesis of this pathological vasculature, most notably neoangiogenesis and postnatal vasculogenesis. These processes may also play a critical role in the resistance to antiangiogenic agents, leading to tumor progression. In particular, vasculogenesis is mediated by endothelial progenitor cells (EPCs), which include cellular subpopulations with different functional capacities. EPCs are able to proliferate, migrate, and differentiate into mature endothelial cells (ECs) in response to tumor growth, promoting the "angiogenic switch" and, consequently, inducing the invasion and metastases of cancer cells. Therefore, vasculogenesis mediated by EPCs represents an intriguing therapeutic target, both in early and late stages of cancer progression, thereby working as potential landmark for synthesizing novel and more effective anti-angiogenic drugs. Here, we aim to focus and to summarize several biological features of EPCs and EPC-based therapeutic approach with potential translation in human clinical trials.