Sir William Osler is one of the most admired and honored physicians in the history of medicine. He influenced the development of medicine in Canada, the United States, and Great Britain, where he held professorships at McGill University, the University of Pennsylvania, Johns Hopkins University, and Oxford University. Through his textbook, The Principles and Practice of Medicine, and other clinical and philosophical writings, he exercised a truly global influence. In this sesquicentennial of his birth, William Osler continues to serve as a model of excellence for the medical profession. This examination of the reasons for his enduring impact reveals a legacy of clinical, scientific, literary, educational, and intraprofessional accomplishments linked to a remarkable personality, and bound together by an extraordinary humanism.