Abstract: Treatment for cancer has been improved over the past few years with the introduction of new approaches to treat various types of tumours, but majority of cancers are still treated with conventional cytotoxic drugs which may be used alone or in combination to improve the cytotoxic effect. However, there is no significant difference in the clinical efficacy among these combinations due to the development of chemoresistance. Drug resistance is the major cause of cancer treatment failure carries a huge burden to patients, healthcare providers and produces a great challenge to the drug developers to overcome this problem. The resistance of cancer cells to powerful chemotherapeutic drugs has become an area of intense investigation. The cancerous cells that develop resistance to chemotherapy over expressed growth factors receptors undergoes mutation resulting in activation of an alternative cell signaling pathways like MAP Kinase, mTOR, Nf-κB which allow them to develop chemoresistance similarly the over expression of anti-apoptotic proteins and escape them from apoptotic cell death contribute to chemoresistance. Objective of this review is to highlight the role of cell signalling pathways to understand the mechanisms underlying chemoresistance and summarizes the potential application of various signalling modulators in combination with chemotherapeutic agents as a novel therapeutic strategy to fight against cancer resistance.