Insulin resistance (IR) and its associated metabolic derangements are known complications of advanced chronic kidney disease (CKD). The etiology of IR in CKD is multifactorial with likely contributions from vitamin D deficiency, obesity, metabolic acidosis, inflammation, and accumulation of 'uremic toxins' leading to acquired defects in the insulin-receptor signaling pathway. An important consequence in end-stage renal disease (ESRD) is its role in the pathogenesis of uremic protein energy wasting, a commonly observed state of metabolic derangement characterized by loss of somatic and visceral protein stores not entirely accounted for by inadequate nutrient intake. In the general population, IR has been associated with accelerated protein catabolism. Among ESRD patients, enhanced muscle protein breakdown has been observed in patients with type 2 diabetes mellitus (DM) compared to ESRD patients without DM. In the absence of DM or severe obesity, IR is detectable in dialysis patients and strongly associated with increased muscle protein breakdown, even after controlling for inflammation. This process appears to be mediated by the ubiquitin-proteasome pathway. Given the high prevalence of protein energy wasting in ESRD and its unequivocal association with adverse clinical outcomes, IR may represent an important modifiable target for intervention in the ESRD population.