The corticomedullary osmolality gradient is the driving force for water reabsorption occurring in the kidney. In the collecting duct, this gradient allows luminal water to move across aquaporin (AQP) water channels, thereby increasing urine concentration. However, this same gradient exposes renal cells to great osmotic challenges. These cells must constantly adapt to fluctuations of environmental osmolality that challenge cell volume and incite functional change. This implies profound alterations of cell phenotype regarding water permeability. AQP2 is an essential component of the urine concentration mechanism whose controlled expression dictates apical water permeability of collecting duct principal cells. This review focuses on changes of AQP2 abundance and trafficking in hypertonicity-challenged cells. Intracellular mechanisms governing these events are discussed and the biological relevance of altered AQP2 expression by hypertonicity is outlined.