Over the course of 38 years, I have engaged in studies of the pathogenesis of obesity and Type II diabetes, which led to the exploration of "resistance" to three important metabolic hormones – insulin, leptin and FGF21. Many of these studies examined both the mechanisms and implications of resistance to the action of these hormones. Indeed resistance to metabolic hormones has proven to be an important feature of disease.  I will first review early studies of insulin resistance caused by immune and genetic interference with insulin action, and review how insights from these rare disorders have, or have not, led the way to our current imperfect understanding of the biochemical and genetic basis for insulin resistance in common forms of obesity and diabetes. I will then review the emergence of leptin as a major new metabolic hormone, assess our understanding of its biologic role, define how “leptin resistance” arises, and why this state may be consistent with the evolutionary role of this hormone. Finally, I will examine the emerging biology of FGF21 as a metabolic regulator and therapeutic agent, including evidence for resistance to some of its actions.