Coronary artery disease (CAD) and peripheral arterial disease (PAD) are significant medical problems worldwide. Although substantial progress has been made in prevention as well as in the treatment, particularly of CAD, there are a large number of patients, who despite maximal medical treatment have substantial symptomatology and who are not candidates for mechanical revascularization. Therapeutic angiogenesis represents a novel, conceptually appealing treatment option. Ad(GV)VEGF121.10 (BIOBYPASS) is an adenovector, carrying the transgene encoding for human vascular endothelial growth factor 121 (VEGF(121)). A number of preclinical studies have demonstrated angiogenic activity of BIOBYPASS, not only anatomically but also functionally. Phase I clinical studies have demonstrated that intramyocardial infection of BIOBYPASS in patients with severe CAD as well as intramuscular injections of BIOBYPASS in patients with severe peripheral vascular disease (PVD) was well tolerated; furthermore, these studies provided some intriguing indications of activity, which led to initiation of major randomized Phase II "proof-of-concept" studies. This paper provides a review of the rationale behind BIOBYPASS as well as a summary of pertinent preclinical and early clinical data.