Pim kinases, also known as Serine/Threonine kinases, are intensively studied protein drug targets in cancer research. They play crucial role in the regulation of signal transduction cascades that promote cell survival, proliferation and drug resistance. Pim kinases are overexpressed in several hematopoietic and solid tumors and support in vitro/in vivo malignant cell growth and survival, through cell cycle regulation and inhibition of apoptosis. Pim kinases do not have an identified regulatory domain, as they are constitutively active. They appear to be critical downstream effectors of a number of oncoproteins. When overexpressed, they mediate drug resistance to agents such as Rapamycin. X-ray crystallographic studies reveal that unlike other kinases, Pim kinases have a hinge region, which forms a unique binding pocket for ATP, offering a target for a large number of potent small-molecule Pim kinase inhibitors. Combination therapy of Pim kinase inhibitors with chemotherapeutic and other kinase modulators seems to produce an additive cytotoxic effect in cancer cells. Though clinical trials have been carried out on the first Pim inhibitory agent, SGI-1776, no concept data could be generated due to its early withdrawal. However, it has helped in accelerating the discovery of several novel Pim inhibitors in recent years. Current research on Pim kinase is expected to lead to a new generation of potent Pim kinase inhibitors with appropriate pharmacological profiles suitable for human cancer therapy in the near future. Herein, we review the synthetic route and mechanistical studies of Pim kinase inhibitors which are currently in human trials.