A longstanding debate remains over whether or not pulsatile flow provides better perfusion during cardiopulmonary bypass (CPB). This paper provides a guide for clinical investigation, as well as current laboratory and clinical evidence concerning pulsatile and non-pulsatile perfusion. This evidence is in the form of in vitro and in vivo experiments and clinical trials. We review the literature and provide personal experience from the Pediatric Cardiac Research Laboratories at the Penn State Hershey Children's Hospital. Pulsatility is emerging as the preferred perfusion method for CPB. Clinical evidence show better cardiac, renal, and pulmonary outcomes in patients receiving pulsatile perfusion. Furthermore, better cytokine, endothelin, and hormone levels and a higher respiratory index are shown in pulsatile perfusion modes compared with non-pulsatile perfusion modes. In recent years, evidence has amounted that supports a shift toward pulsatility in these procedures over non-pulsatility. Currently, more evaluation of circuit components and patient outcomes is needed.