The concept that the immune system can communicate with peripheral sensory neurons to modulate pain is based mostly on documented interactions between opioid ligands and receptors. Such findings may have broad implications for the development of safer pain medication. Innovative strategies take into account that analgesics should be particularly active in pathological states rather than producing a general suppression of the central nervous system, as with conventional morphine- or cannabinoid-like drugs. Inflammation of peripheral tissue leads to increased functionality of opioid receptors on peripheral sensory neurons and to local production of endogenous opioid peptides. In addition, endocannabinoids were detected in leukocytes, but their role in pain modulation has yet to be addressed. Future aims include the development of peripherally restricted opioid agonists, selective targeting of opioid-containing immune cells to sites of painful injury, and the augmentation of peripheral ligand and receptor synthesis (e.g., by gene therapy). Similar approaches may be pursued for cannabinoids. The ultimate goal is to avoid detrimental side effects of currently available analgesics such as respiratory depression, cognitive impairment, addiction, gastrointestinal bleeding, and thromboembolic complications.