Surgery is well-known to result in the suppression of some immune functions; however, the role of perioperative pain has only recently been studied. Pain-relieving anesthesia techniques and perioperative analgesia provide some protection against surgery-induced immune suppression and infectious surgical sequelae, although few studies also assess postoperative pain. Attributing a biological consequence to the observed immune alterations remains an issue in human studies, and the use of immune sensitive tumor models in animals enables the linking of immune changes with disease and a means by which to explore causal relationships among surgery-related pain, immune function, and metastatic development. There is strong evidence in animals that pain-relieving interventions significantly reduce the tumor-enhancing effects of undergoing and recovering from surgery. It cannot be assumed that animal findings are directly applicable to the human condition; however, if such relationships hold in humans, perioperative pain management becomes an important strategy for reducing postoperative sequelae.