The loss of corticomedullary differentiation (CMD) on contrast-enhanced CT reflects disruption of the physiologic perfusion gradient between the renal cortex and medulla. While benign and inflammatory disorders remain the most frequent causes, malignant renal processes constitute an important subset of pathology in which recognition of altered CMD may have major diagnostic and therapeutic implications. In neoplastic presentations, diffuse or segmental alterations in CMD arise from replacement, compression, or infiltration by tumor, or from the interplay of vascular and urinary obstructive mechanisms. Characteristic enhancement kinetics across the different enhancement phases may allow differentiation among various renal masses. This pictorial review focuses on the imaging hallmarks and pathophysiologic correlates of malignant renal neoplasms with associated altered CMD, highlighting multiphasic CT patterns, representative cases, and diagnostic pitfalls.