Opioids have been used as pain control medications for thousands of years. Opioids are highly effective analgesics clinically available for controlling moderate and severe pain. Recent genetic knockout and knockin studies have definitively demonstrated that the analgesic effect is mediated through opioid receptors. In addition to their analgesic effect, opioids also have the potential to develop tolerance and physical dependence. Moreover, opioids can modulate cell proliferation and survival. Attempts to design better opioid drugs to eliminate or diminish these undesirable effects for clinical benefits have achieved limited success. In recent years, investigation of the effects of opioid-mediated cell proliferation and survival has been very active, resulting in many publications. However, the molecular targets of such non-analgesic effects are complex. Several important pathways that control cell proliferation, survival, and apoptosis have been reported to be associated with the non-analgesic effects, which may be mediated through both opioid receptor signaling and other non-opioid receptor molecular entity-mediated signaling. This review tries to bring the attention of the medicinal chemistry community to new developments and advances in the research areas of opioid-mediated cell proliferation and survival. Further investigation of the molecular mechanism of these non-analgesic opioid effects may eventually yield useful information such as new drug targets, which may be explored to benefit for clinical treatments such as targeted cancer therapy, cancer pain management, regeneration of neurons, and recovery from drug addiction.