Analysis of the molecular mechanisms governing the ability of IL-10 to keep inflammation under control has highlighted the existence of a great degree of plasticity and specificity with regard to innate immune cells. In this respect, neutrophils represent a perfect example of innate immune cells conditioned by external signals (for instance, by LPS), as well as by intracellular regulatory pathways, that render them optimally responsive to IL-10 only when required. The focus of this review are the recent experimental findings that have uncovered the sophisticated and complex molecular mechanisms responsible for the modulation of pro- and anti-inflammatory cytokine production by IL-10 in neutrophils and other innate immune cells. Understanding how IL-10 exerts its anti-inflammatory response, particularly in the case of neutrophils, will provide novel clues leading, hopefully, to the therapeutic control of neutrophil-driven inflammatory reactions, such as septic infections, rheumatoid arthritis, osteoarthritis and chronic obstructive pulmonary disease.