Objective: Although tumor necrosis factor (TNF) is a well-known inflammatory cytokine in the pathological development of various human diseases, its physiological roles are not widely understood nor appreciated. The molecular mechanisms underlying spinal manipulation therapy (SMT) remain elusive. The relationship between TNF and SMT is unclear. Thus, we performed this literature review to better understand TNF physiology and its potential relationship with SMT, and we propose a novel mechanism by which SMT may achieve clinical benefits by using certain beneficial features of TNF. Methods: We searched several databases for relevant articles published between 1975 and 2015 and then reexamined the studies from current immunophysiological perspectives. Results: The history and recent progresses in TNF physiology research were explored. Conflicting reports on the relationship between TNF and SMT were identified. Based on the newly discovered interaction between TNF and regulatory T cells, we proposed a putative biphasic TNF response to SMT, which may resolve the conflicts in the reported observations and interpretations. Conclusion: The current literature about TNF informed our discussion of new physiological roles for TNF, which may help to better understand the physiological effects of SMT.