For the Inaugural Radcliffe Lecture 2014 Professor Hugh Watkins explores the success and limitations of genome sequencing in simple Mendelian diseases and in complex disorders, against the backdrop of his ground breaking research into heart disease. The Radcliffe Lecture series profiles the astonishing range of work being done in the departments which constitute the Medical Sciences Division at Oxford which is an internationally recognised centre of excellence for biomedical and clinical research and teaching and is the largest of the four academic divisions within the University. The Division comprises 16 departments, and their constituent units, institutes and centres, spread across three sites in Oxford and includes numerous clinical research units in Africa and Asia. Over 4800 academics, researchers and administrative staff, 1400 graduate and 1600 undergraduate students, and 380 NHS clinicians and GPs together contribute to our extensive and exemplary research, teaching and clinical portfolios. We aim to be the best university biomedical institution in Europe and amongst the best five biomedical institutions in the world, and have been ranked number one for the last four years in the Times Higher Education World University Rankings for clinical, pre-clinical and health sciences - the only non-North American institution to be top-ranked by THE in any subject discipline. The departments carry out research, teaching and clinical work across the entire spectrum of the medical sciences.