Few interventions and treatments for premature infants have undergone the rigors of a randomized controlled trial (RCT), the cornerstone of evidence-based healthcare. Multiple barriers in establishing a quality evidence base for the care of preterm infants are examined including the systematic exclusion of children from drug trials, vulnerability of the infants, burden to families of the consent process for RCTs, and the lack of standard measurements and subgroup definitions that impede systematic reviews. Delays in getting evidence into practice are highlighted, including clinician knowledge of existing evidence, attitudes about the evidence, and behavior. Landmark trials are used as examples. Finally, a call for the research community to develop guidance on good clinical research practice for preterm infants is offered that will allow the synthesis of the totality of evidence. (Contains 1 table and 1 figure.)