It is now widely recognized that neutrophils are highly versatile and sophisticated cells that display de novo synthetic capacity and may greatly extend their lifespan. In addition, concepts such as “neutrophil heterogeneity” and “neutrophil plasticity” have started to emerge, implying that, under pathological conditions, neutrophils may differentiate into discrete subsets defined by distinct phenotypic and functional profiles. A number of studies have shown that neutrophils act as effectors in both innate and adaptive immunoregulatory networks. In fact, once recruited into inflamed tissues, neutrophils engage into complex bidirectional interactions with macrophages, natural killer, dendritic and mesenchymal stem cells, B and T lymphocytes, or platelets. As a result of this cross-talk, mediated either by contact-dependent mechanisms or cell-derived soluble factors, neutrophils and target cells reciprocally modulate their survival and activation status. Altogether, these novel aspects of neutrophil biology have shed new light not only on the potential complex roles that neutrophils play during inflammation and immune responses, but also in the pathogenesis of several inflammatory disorders including infection, autoimmunity, and cancer.