The interplay between pro- and anti-inflammatory mechanisms during inflammatory and immune responses is critical for avoiding excessive tissue damage. Extracellular nucleotides (e.g., adenosine 5′-triphosphate) may represent constitutive signals that can alert the immune system of abnormal cell death. Relatively high doses of nucleotides induce rapid release of proinflammatory mediators and favor pathogen killing. However, recent findings on antigen presenting cells, particularly dendritic cells, revealed a more complex role for these molecules. Chronic exposure to low-dose nucleotides can redirect cellular responses to prototypic activation stimuli, leading to suppressed inflammation and immune deviation.