In this issue: harnessing immunity against difficult targets, through the CD40-CD40L pathway.

This issue highlights translational aspects related to the CD40-CD40L pathway, a veritable master-switch at the interface between the innate and adaptive immunity. From direct targeting of CD40 onto tumor cells to licensing professional antigen presenting cells (APC), and from in vivo activation of immune effectors to enabling adoptive cell immune interventions, this pathway already shows translational promise in oncology and infectious diseases. In light of the pivotal nature and versatility of the target, the authors discuss a diverse range of options to design and advance novel, safe and effective immune interventions or combinatorial therapies involving CD40 agonistic engagement.