Recent insights into the role of complement anaphylatoxins C3a and C5a in cancer provide new opportunities for the development of innovative biomarkers and therapeutic strategies. These two complement activation products can maintain chronic inflammation, promote an immunosuppressive microenvironment, induce angiogenesis, and increase the motility and metastatic potential of cancer cells. Still, the diverse heterogeneity of responses mediated by these peptides poses a challenge both to our understanding of the role played by these molecules in cancer progression and to the development of effective treatments. This review attempts to summarize the evidence surrounding the involvement of anaphylatoxins in the biological contexts associated with tumor progression. We also describe the recent developments that support the inhibition of anaphylatoxins, or their cognate receptors C3aR and C5aRI, as a treatment option for maximizing the clinical efficacy of current immunotherapies that target the PD-1/PD-L1 immune checkpoint. (C) 2017 Elsevier Ltd. All rights reserved.