Careful reviews and meta-analyses have made valuable contributions to understanding the efficacy of psychosocial interventions for cancer patients. An important next step is to determine the mediators that explain the influence of efficacious interventions on outcomes. This systematic review summarizes tests of mediating variables from twenty-two projects conducted from 1989-2010. Although all authors provided some type of rationale for considering particular mediating relationships, the investigations varied widely with respect to the extent to which formal theoretical constructs were tested, the type and goals of the interventions studied, and the broad types of outcomes and potential mediators examined. Although there was some evidence supporting selected mediating relationships, with positive findings often found when mediating variables represented behaviors targeted by an intervention, the findings were mixed. Expanding the focus of research to include mechanisms in psychosocial oncology intervention research is necessary for providing a unified picture of how mediating relationships may be operating in this field.