Revascularization by either bypass surgery or endovascular recanalization is considered the first-choice treatment in patients with critical limb ischemia (CLI). Only conservative options are left in CLI patients in whom successful revascularization strategies are not possible: in these patients, at present, prostanoids (iloprost and prostaglandin [PGE1]) represent the pharmacological treatment of choice. Iloprost resulted more effective than PGE1, in a 6 month follow-up, in both limb savage and in prevention of cardiovascolar death, either in diabetic or non diabetic patients with unreconstructable CLI. In our experience, in patients who have responded to a first cycle of therapy (early responders), performed for at least 2-3 weeks, cyclic annual further treatments with iloprost are usually able to stabilize arterial disease, with a regression to Fontaine II stage and, in absence of further arterial complications, with complete limb preservation for an unlimited period of time. In non-responder patients, who are not urgently supposed to undergo amputation, a second cycle of iloprost carried out within few months from the first one, is able to increase the percentage of responders to prostanoids (late responders). Vice versa, in non-responders to repeat prostanoid cycles, it is useful to verify the outcomes of further attempts at saving, the symptomatic limb by surgical or endovascular re-timing, spinal cord stimulation, gene or stem cell therapy. Our recent better outcomes are related to earlier microvascular diagnosis and to earlier, repeat, pharmacological treatments with iloprost. Transcutaneous oxygen and carbon dioxide monitoring improves the possibility of an earlier diagnosis of microvascular damages and categorizes CLI patients in responders and non-responders after prostanoid treatments.