In the latest issue of Nature Immunology, Piccolo et al.1 elegantly explored the effect of coexisting interferon-γ (IFN-γ) and interleukin 4 (IL-4) antagonistic signals on macrophage transcriptional and epigenetic profiles and, interestingly, identified a plastic cross-talk as opposed to mutually exclusive programs between M1 and M2 polarized macrophages. Their results support the fascinating hypothesis that transcriptional and epigenetic reprogramming overcame genetics to drive the evolution of eukaryotic organisms. A rapid reshaping of chromatin acetylation redirected the expression of hundreds of genes under the control of a few transcription factors in response to two coexisting but opposing signals that indicated inflammation and its resolution simultaneously.