Introduction.Regenerative therapies have recently gained popularity in orthopedics and we overview the available scientific evidence on the topic. Methods. A narrative literature review with three relevant case reports. Results. Scientific evidence on regenerative medicine is growing, but some established findings can de underscored. First, a persistent inflammatory response plays a key role in tissue reparation because it inhibits the activity of stem cells: therefore, regenerative therapy is effective if it can reduce local inflammation, thus allowing stem cells to regenerate the damage. Secondly, the regenerative potential of stem cells is regulated by local immunity and, in particular, by macrophages, which are involved in damage response and tissue regeneration. Among others, the concentrate of peripheral blood mononuclear cells (PB-MNCs), rich in monocytes, lymphocytes, and CD34+ hematopoietic stem cells, appears an interesting cell-based therapeutic strategy to promote tissue regeneration in several orthopedic disorders. Discussion. Regenerative medicine can offer new valuable therapeutic strategies. In particular, potential applications of PB-MNCs in foot and ankle disorders are discussed with some explanatory cases from clinical practice.