Selective coronary angiography was originally performed through open brachial arteriotomy. Thereafter, the percutaneous Seldinger technique and the use of preformed Judkins-type catheters popularized the femoral approach. More recently, after the first report of successful coronary angiography by the transradial approach in 1989, the radial artery has been increasingly used as an alternative access site. The main advantage offered by the transradial approach is represented by the very low (< 1%) incidence of relevant vascular access site complications, which on the contrary occur in about 3% to 7% of patients undergoing procedures through the femoral route. The main disadvantage is a higher incidence of procedural failure that leads to a crossover to the femoral route. In this review, we examine the available evidence on transradial and transfemoral approach advantages, disadvantages, and complications in coronary angiography and intervention. Their use in the acute myocardial infarction setting and other situations is described. Vascular closure device usefulness is also considered.