The evolution of clinical research traverses a long and fascinating journey. From the first recorded trial of legumes in biblical times to the first randomized controlled of trial of streptomycin in 1946, the history of clinical trial covers a wide variety of challenges – scientific, ethical and regulatory. The famous 1747 scurvy trial conducted by James Lind contained most elements of a controlled trial. The UK Medical Research Council’s (MRC) trial of patulin for common cold in 1943 was the first double blind controlled trial. This paved the way for the first randomized control trial of streptomycin in pulmonary tuberculosis carried out in 1946 by MRC of the UK. This landmark trial was a model of meticulousness in design and implementation, with systematic enrolment criteria and data collection compared with the ad hoc nature of other contemporary research. Over the years, as the discipline of controlled trials grew in sophistication and influence, the streptomycin trial continues to be referred to as ground breaking. The ethical advances in human protection include several milestones – Nuremberg Code, Declaration of Helsinki, Belmont Report, and 1996, International Conference on Harmonization Good Clinical Practice guidance. In parallel to ethical guidelines, clinical trials started to become embodied in regulation as government authorities began recognizing a need for controlling medical therapies in the early 20th century. As the scientific advances continue to occur, there will be new ethical and regulatory challenges requiring dynamic updates in ethical and legal framework of clinical trials.