Malpighian tubules are a key part of the insect excretory system and play critical roles in various physiological processes including salt and water balance, xenobiotic detoxification, and nitrogenous waste excretion. Essential to nearly all of these processes is transepithelial fluid secretion, which generates a primary urine compartment for the deposition of excess ions, water, and metabolic wastes in the hemolymph. Transepithelial fluid secretion is of especial importance to mosquitoes, which encounter unique challenges to water balance associated with their amphibious life cycle and the hematophagy of adult females. The Malpighian tubules of mosquitoes secrete fluid via a two-step process; i.e., cations (primarily Na+ and K+) and anions (primarily Cl-) are transported from the hemolymph to the tubule lumen, which then generates a favorable osmotic gradient for water to follow. Here we provide an update on recent advances to our understanding of molecular mechanisms involved with the transepithelial transport of cations in the Malpighian tubules of mosquitoes. We will focus on new insights into the functional and regulatory properties of inward rectifier K+ (Kir) channels and cation chloride cotransporters (CCCs) that are expressed in mosquito Malpighian tubules. We will discuss how these mechanisms may contribute to transepithelial fluid secretion in mosquito Malpighian tubules as well as elements of the mosquito life cycle.