Spindle poisons/anti-microtubule drugs are established chemotherapy drugs. These drugs primarily target microtubules and mitotic spindles, activate spindle assembly checkpoint (SAC), resulting in caspase-mediated cell death. However, the terminal phenotypes of drug-treated cells are surprisingly heterogeneous ranging from mitotic catastrophe to apparent senescence, suggesting that input from a variety of signaling pathways influences the cell death process. In recent years, studies revealed several signaling pathways that modulate the efficacy of spindle poisons. In this review, we discuss the genes and pathways whose inhibition or overexpression modulates spindle poison sensitivity. These genes cluster to (i) microtubule, microtubule associated proteins (MAPS) and actin cytoskeleton regulators, (ii) the SAC components, (iii) signaling proteins, (iv) chaperones, (v) cell cycle regulators, (vi) proteasome components, (vii) transcription factors and nuclear receptors, and (viii) apoptotic factors. These gene products would be potential targets for drugs to be combined with spindle poisons. Expression status of these genes would also serve as a prognostic marker for spindle poison- mediated chemotherapy. Understanding signaling pathways involved in drug efficacy will aid to rationally develop synergistic chemotherapy strategy.