Proviral integration site for Moloney murine leukemia virus (Pim) kinases is a potential therapeutic target in both hematological and solid tumors, and is up-regulated in various cancer types. In certain cases, their expression levels are positively correlated with poor clinical outcome. A number of selective Pim kinase inhibitors are under development and a few are in clinical trials. Investigations of the mechanism of actions of these drugs have demonstrated that by inhibiting Pim kinases, processes such as transcription, translation, cell cycle progression, cell survival and drug resistance are affected. Pim kinases can be upregulated by multiple growth factors, cytokines, and chemokines, which also activate redundant pathways such as phosphatidylinositide 3-kinases/protein kinase B/mammalian targets of rapamycin, and mitogen-activated protein kinases. Interestingly, Pim kinases also share substrates with these parallel pathways. To overcome this challenge, Pim kinase inhibitors were tested in combination with other therapeutic agents based on their unique mechanism of actions. Based on existing literature, we identified studies where Pim kinase inhibitors were part of the combination strategies that used targeted agents or broad-spectrum chemotherapeutic drugs (including FDA-approved agents). The addition of Pim kinase inhibitors to these treatment strategies leads to additive to synergistic cytotoxic effect in cancer cells. Depending on the compound, combination results in sequential or complementary blockage or downregulation of oncogenic pathway. In summary, these studies provide evidence for developing mechanism-based combination therapies with Pim kinase inhibitors to treat cancers.