Systemic toxicity still prevents full clinical application of cytokines such as type I Interferons (IFNs), Interleukin-1 (IL-1) or Tumor Necrosis Factor (TNF). Whereas immunocytokines (cytokines equipped with a targeting antibody) display a 10-fold increased activity on target cells, off-target side effects experienced by patients are expected to remain a major obstacle. AcTakines (Activity-on-Target cytokines) resemble classical immunocytokines but employ mutant cytokines with reduced binding affinity for their cognate receptor complex. These modifications cause AcTakines to remain inactive 'en route' through the body and to unveil their activity only on specifically targeted cell types which greatly reduces undesired side effects. This concept is being developed together with Gilles Uzé (CNRS, Montpellier). See also Garcin et al. (2014, Nature Communications).