Abstract: The mu opioid receptor (MOR) is the main target for opiate analgesics such as morphine and fentanyl. The classical opioid analgesics are widely used clinically for moderate to severe pain, however, their long-term use often induces antinociceptive tolerance and addiction, together with side-effects such as dizziness, nausea, vomiting, constipation, pruritus and respiratory depression, which undermine their clinical application. Significant progress has been made in recent years in the research on multi-target compounds for the effective segregation of analgesia from unwanted effects. These multi-target ligands targeting MOR and other receptors produce effective antinociceptive effects with reduced side-effects on antinociceptive tolerance, addiction, respiratory depression and constipation. This article reviews the designing strategies and pharmacological activities of the multi-target peptide ligands, with an aim to provide a new approach to the development of peptide-based analgesics.