This review outlines recent advances related to the molecular mechanisms and pathways of aquaporin-2 (AQP2) water channel trafficking. AQP2 is a fascinating protein, whose sorting signals can be interpreted by different cell types to achieve apical or basolateral membrane insertion, in both regulated and constitutive trafficking pathways. In addition to the well-known cAMP-mediated, stimulatory effect of vasopressin on AQP2 membrane insertion, other signaling and trafficking events can also lead to AQP2 membrane accumulation via cAMP-independent mechanisms. These include 1) elevation of cGMP, mediated by sodium nitroprusside (a nitric oxide donor), atrial natriuretic factor, andl-arginine (via nitric oxide synthase); 2) disruption of the actin cytoskeleton; and 3) inhibition of the clathrin-mediated endocytotic arm of the AQP2 recycling pathway by dominant-negative dynamin expression and by membrane cholesterol depletion. Recent data also indicate that AQP2 recycles constitutively in epithelial cells, it can be inserted into different membrane domains in different cell types both in vitro and in vivo, and these pathways can be modulated by factors including hypertonicity. The roles of accessory proteins, including small GTPases and soluble N-ethylmaleimide-sensitive factor attachment protein receptor proteins in AQP2 membrane insertion, are also being uncovered. Understanding cAMP-independent mechanisms for membrane insertion of AQP2 is especially relevant to the therapeutic bypassing of the mutated, dysfunctional vasopressin receptor in patients with X-linked nephrogenic diabetes insipidus.