Over the years, clinical registries and randomized controlled trials gained acceptance. With increasing experience, it was possible to obtain knowledge of benefits and limitations in both designs. During the last years, the research focus was placed on new study concepts such as register-based randomized controlled trials intending to merge the benefits of evidence obtained by RCTs and clinical registers. In this review, we aim to provide an overview of the evolution and the present stage of clinical trials. While doing so, we outline past experience and look ahead toward improving models for high-quality clinical trials.