Peripheral arterial disease (PAD) is a major health care problem. There have been limited advances in medical therapies, and a huge burden of symptomatic patients with intermittent claudication and critical limb ischemia who have limited treatment options. Angiogenesis is the growth and proliferation of blood vessels from existing vasculature. For approximately 2 decades, “therapeutic angiogenesis” has been studied as an investigational approach to treat patients with symptomatic PAD. Despite literally hundreds of positive preclinical studies, results from human clinical studies thus far have been disappointing. Here we present an overview of where the field of therapeutic angiogenesis stands today and examine lessons learned from previously conducted clinical trials. The objective is not to second-guess past efforts but to place the lessons in perspective to allow for trial success in the future to improve agent development, trial design, and ultimately, clinical outcomes for new therapeutics for PAD.