A growing body of information indicates that release of intracellular nucleotides represents an important way to modulate several cell pathways in physiological or pathological conditions. Nucleotides released as a consequence of cell damage, cell stress, bacterial infection, or other noxious stimuli signal at a class of plasma membrane receptors--P2 receptors--activating diverse intracellular pathways in many tissues and organs. For example, nucleotides secreted in the airway system control chloride/liquid secretion, goblet cell degranulation, and ciliary beat frequency. Several studies indicate that nucleotides play a role in airway diseases through their action on multiple cell types, including mast cells, dendritic cells, neurons, and eosinophils. Recent work by us and other groups led to the identification and characterization of P2 receptors expressed by human eosinophils. In this review, we will summarize recent developments in this field and put forward a hypothesis about the role of P2 receptors in pathophysiological conditions where eosinophils are major players.