Sir Harold Himsworth first observed and articulated the phenomenon of insulin resistance in the late 1930s. Although a long delay followed before his observations were acknowledged and enshrined in formal diagnostic classifications of diabetes mellitus, insulin resistance-related pathology in the early 21st century poses one of the major global healthcare challenges for contemporary physicians. Whilst insulin resistance is closely related to obesity and decreased physical fitness, despite intensive investigation it has proved extremely challenging to discriminate key events in its causation from epiphenomena, many related to compensation for the primary defect. Thus, a complete account of the molecular pathogenesis of insulin resistance-related diseases remains elusive. One approach circumventing such problems is the study of patients with single gene defects causing severe insulin resistance. In such patients the primary defect is known, and thus lessons may be learned about human physiology from detailed physiological study allied to knowledge of the function of the mutated protein. This review discusses developments in understanding of monogenic severe insulin resistance since discovery of the first insulin receptor mutations in 1988 and reviews the physiological lessons learnt, including the critical role of adipose tissue in human metabolic health and the meaning and importance of 'partial' insulin resistance for major human disease.