Drugs targeting the μ-opioid receptor (μOR) are the most effective analgesics but are associated with the severe side effects behind the current opioid epidemic. Here I will present our work on the structural and mechanistic basis of action of µOR agonists with different safety profiles.  I will discuss how cryo-EM structures, molecular dynamics simulations and cell-based assays suggest that drugs engaging different parts of the μOR orthosteric pocket may lead to distinct signaling outcomes.