Insulin resistance (IR) is an early metabolic alteration in CKD patients, being apparent when the glomerular filtration rate is still within the normal range and becoming almost universal in those who reach the ESKF. The skeletal muscle represents the primary site of IR in CKD and post-receptor alterations are recognized as the main defect underlying IR in this condition. Estimates of IR based on fasting insulin concentration are easier but may not be adequate in CKD patients because renal insufficiency reduces insulin catabolism. The hyperinsulinemic euglycemic clamp is the gold standard for the assessment of insulin sensitivity. The etiology of IR in CKD is multifactorial in nature and may be secondary to disturbances which are prominent in renal diseases, including chronic inflammation, oxidative stress, vitamin D deficiency, adipokines derangement and altered gut microbiome. IR contributes to renal disease progression by worsening renal hemodynamics by various mechanisms, including activation of the sympathetic nervous system, sodium retention and downregulation of the natriuretic peptide system. IR has been solidly associated with intermediate mechanisms leading to cardiovascular (CV) disease in CKD including left ventricular hypertrophy, vascular dysfunction and atherosclerosis. However, it remains unclear whether IR is an independent predictor of mortality and CV complications in CKD. Because IR is a modifiable risk factor and its reduction may lower CV morbidity and mortality, unveiling the molecular mechanisms responsible for the pathogenesis of CKD-related insulin resistance is of importance for the identification of novel therapeutic targets aimed at reducing the high CV risk of this condition.