Cancer immunotherapy may become the treatment backbone in many cancers over the next decade. The demonstration that an intratumor TH1 immune polarity is prognostic of good clinical outcome and the recent success with co-immune checkpoint blockade in humans now sets the stage for rational tailoring of immunotherapies to treat specific cancer types. The recently approved anti-PD-1 monoclonal antibody (mAb)(pembrolizumab) and other mAbs targeting PD-L1 have revolutionized the field. Pre-clinical data and combinations between anti-CTLA-4 (ipilimumab) and anti-PD-1 (Nivolumab) in advanced malignant melanoma demonstrate the anti-tumor potential and dangers of targeting more than one immune evasion pathway. There are four different types of tumor microenvironment based on the presence or absence of tumor infiltrating lymphocytes and programmed death-ligand 1 (PD-L1) expression. This stratification may be an approach for rationally designing ideal combinations between various new immunotherapies and conventional cancer treatments. This seminar will discuss our recent work to determine which tumors are responsive to anti-PD-1 and what pathways are necessary for, or an impediment to, anti-PD-1 anti-tumor activity. Our efforts to pre-clinically examine two new target pathways including immune checkpoints CD96/TIGIT and the immune suppressive metabolite adenosine will be described. Their combination with anti-PD-1 therapies will be detailed. Further, the ability of some targeted therapies to act in part via host immunity has created opportunities to rationally combine these approaches with immunotherapy in humans. These and other pre-clinical studies of combinations that concurrently relieve Treg- and M2 macrophage-mediated immune suppression will be discussed. Mouse models for combination treatment sequencing in the context of adjuvant therapy and safety in relation to immune related adverse events will be presented.