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Kidneys accomplish many important physiological tasks, ranging from the continuous blood filtration and consequent formation of urine, detoxification from endogenous and exogenous substances, production of active and inactive hormones (e.g., Vitamin D, Erythropoietin, and renin), and maintenance of the electrolytes balance. However, its function can be readily impaired by many pathogen noxae, leading to the so-called chronic kidney disease (CKD). This condition can be clinically assessed by the estimation of the glomerular filtration rate (eGFR), an indirect index of the renal function, that do not give any further information of which kind of injury affects the kidney. For this reason, the gold standard to determine the CKD cause is represented by the renal biopsy and the histomorphological criteria are essential for the interpretation of the tissue sample. In this chapter, the clinical and histopathological aspects of CKD will be discussed, with a final section on the future challenges represented by the molecular analysis and digital pathology in renal disease.