Intercellular communications are fundamental for a correct progression of immuno inflammatory responses. Major messengers in this network of information are cytokines, secretory proteins produced by immune and inflammatory cells. Blocking the function of pro-inflammatory cytokines has entered the clinical arena of treating autoimmune diseases. However, many cytokines including Interleukin (IL)-1, IL-18, HMGB1, belong to the family of “leaderless secretory proteins”, that leave the cells through pathways independent from the classical Endoplasmic Reticulum (ER)-Golgi route. Thus, a successful outcome of an approach aimed at inhibiting cytokine activity requires a clear definition of the mechanisms controlling their release. In this article we will review current hypotheses on the mechanisms underlying non classical secretion and discuss their implications in the regulation of the inflammatory and immune response. In particular, we will dissect the sequence of events required for IL-1β secretion and describe some members of the molecular machinery involved, which could provide novel targets whereby control of IL-1β production may be achieved.