Circulating concentrations of canonically pro- and anti-inflammatory cytokines are commonly measured when evaluating the anti-inflammatory effects of exercise. An important caveat to interpreting systemic cytokine concentrations as evidence for the anti-inflammatory effects of exercise is the observed dissociation between circulating cytokine concentrations and cytokine function at the tissue/cellular level. The dichotomization of cytokines as pro- or anti-inflammatory also overlooks the context-dependence of cytokine function, which can vary depending on the physiological state being studied, the cytokine's cellular source/target, and magnitude of cytokine responses. We re-evaluate our current understanding of anti-inflammatory cytokine responses to exercise by highlighting nuances surrounding the interpretation of altered systemic cytokine concentrations as evidence for changes in inflammatory processes occurring at the tissue/cellular level. We highlight the lesser known pro-inflammatory and immunostimulatory actions of the prototypical anti-inflammatory cytokine, interleukin (IL)-10, including: the potentiation of interferon gamma production during endotoxemia, CD8+ T cell activation in tumor bearing rodents and cancer patients in vivo, and CD8+ T lymphocyte and natural killer cell activation in vitro. IL-10's more well-established anti-inflammatory actions can also be blunted following exercise training and under chronic inflammatory states such as type 2 diabetes (T2D) independent of circulating IL-10 concentrations. The resistance to IL-10's anti-inflammatory action in T2D coincides with blunted STAT3 phosphorylation and can be restored with small-molecule activators of IL-10 signaling, highlighting potential therapeutic avenues for restoring IL-10 action. We posit that inferences based on altered circulating cytokine concentrations alone can miss important functional changes in cytokine action occurring at the tissue/cellular level. Abstract Figure Legend. Chronic inflammation is linked to the development and progression of various cardiometabolic diseases. Increased circulating concentrations of classical "anti-inflammatory" cytokines such interleukin-10 (IL-10) are frequently interpreted as evidence for the ability of exercise to reduce inflammation. However, there are several scenarios where circulating IL-10 concentrations may not reflect a reduction in inflammation at the cellular level, including: 1) the ability of IL-10 to act as an immunostimulatory and pro-inflammatory molecule under specific contexts, 2) a reduction in the ability of IL-10 to inhibit cellular inflammation following short-term exercise training, and 3) a hyporesponsiveness to IL-10 action under states of chronic metabolic stress or inflammation. These scenarios highlight situations where interpreting changes in circulating IL-10 concentrations as support for the anti-inflammatory effects of exercise may be inappropriate, as an increase in IL-10 may not necessarily represent a reduction in inflammatory processes occurring at the cellular level.