Eur J Clin Invest 2012; 42 (6): 686–691 Background  The process of extravasation of leucocytes from the vasculature into an infected, inflamed or injured tissue, designated the leucocyte adhesion cascade, is a major process in innate and adaptive immunity. In every immune process, both agonists and inhibitors, that is, positive and negative regulators, exist. Materials and methods  It was only recently that endogenous inhibitors of the leucocyte adhesion cascade were identified, whereas many selectin, integrin and immunoglobulin superfamily adhesion receptors as well as chemokines and chemokine receptors promoting leucocyte recruitment have been described over the last three decades. Endogenous negative regulators include for instance pentraxin‐3 (PTX‐3) that blocks selectin‐dependent leucocyte rolling, or the endothelium‐derived developmental endothelial locus‐1 (Del‐1) that antagonizes beta2‐integrin‐mediated firm adhesion of leucocytes to the endothelium. Conclusions  As leucocyte infiltration is a major therapeutic target in inflammatory and autoimmune disease, it becomes obvious that such endogenous anti‐adhesive and anti‐inflammatory agents may represent an attractive novel therapeutic platform for inflammatory and immune disorders. This review focuses on these novel endogenous inhibitors of leucocyte recruitment.