The CD40-CD40 ligand (CD40L) pathway is a backbone of communication between cells of the immune system. It makes it possible to generate a proinflammatory signal and thus participates in the pathogenesis of dysimmune diseases, transplant rejection and atherosclerosis. Because of this therapeutic target of choice, several generations of anti-CD40L monoclonal antibodies have emerged since the 1990s. The first generation of antibodies was responsible for thromboembolic toxicity for which the mechanisms are starting to be defined. New generations of antibodies were designed to overcome this toxicity and are still being developed in lupus, rheumatoid arthritis, Sjogren’s syndrome or immunologic thrombocytopenia. In addition to these targeted therapies, there are data suggesting the impact of several drugs among molecules used in cardiology and clinical immunology on the level of CD40L. The objective of this review is to recall the clinical issues related to the CD40-CD40L axis and to present current or future treatments that block CD40L which would allow clinicians to diversify their options for managing dysimmune diseases.Copyright © 2021 Société Nationale Française de Médecine Interne (SNFMI). Published by Elsevier Masson SAS. All rights reserved.