Critical limb ischemia (CLI) continues to form a substantial burden on Western health care. Despite recent advances in surgical and radiological vascular techniques, a large number of patients is not eligible for these revascularisation procedures and faces amputation as their ultimate treatment option. Growth factor therapy and stem cell therapy - both therapies focussing on augmenting postnatal neovascularisation - have raised much interest in the past decade. Based on initial pre-clinical and clinical results, both therapies appear to be promising strategies to augment neovascularisation and to reduce symptoms and possibly prevent amputation in CLI patients. However, the underlying mechanisms of postnatal neovascularisation are still incompletely understood. Both fundamental research as well as large randomised trials are needed for further optimisation of these treatment options, and will hopefully lead to needed advances in the treatment of no-option CLI patients in the near future.