About 35% of patients affected by erectile dysfunction (ED) do not respond to oral phosphodiesterase-5 inhibitors (PDE5i) and more severe vasculogenic refractory ED affects diabetic patients. Innovative approaches, such as regenerative therapies, including stem cell therapy (SCT) and platelet-rich plasma (PRP), are currently under investigation. Recent data point out that the regenerative capacity of stem cells is strongly influenced by local immune responses, with macrophages playing a pivotal role in the injury response and as a coordinator of tissue regeneration, suggesting that control of the immune response could be an appealing approach in regenerative medicine. A new generation of autologous cell therapy based on immune cells instead of stem cells, which could change regenerative medicine for good, is discussed. Increasing safety and efficacy data are coming from clinical trials using peripheral blood mononuclear cells to treat no-option critical limb ischemia and diabetic foot. In this review, ongoing phase 1/phase 2 stem cell clinical trials are discussed. In addition, we examine the mechanism of action and rationale, as well as propose a new generation of regenerative therapies, evolving from typical stem cell or growth factor to immune cell-based medicine, based on autologous peripheral blood mononuclear cells (PBMNC) concentrates for the treatment of ED.