Sugarcane is an economically important crop plant under the family of Poaceae. It provides approximately 80% of sugar required for human consumption in the world. It is also used as a raw substance for bioethanol production that is a renewable energy source alternative to hazardous fossil fuels. However, various biotic stresses caused by insects, and fungal, bacterial, and other microbial pathogens may restrict sugar yield from sugarcane to a large extent. Crop plants possess a range of signal transduction and perception networks as a complex defense mechanism in response to these biotic stresses. Especially, transcription factors (TFs), which are triggered by various signal transduction pathways, can potentially improve crop yields by regulating the transcription efficacy of target gene/genes via indirect or direct interaction with cis-acting factors. Nevertheless, literature on TFs in stress tolerance in sugarcane is limited though several TFs of various other plants of the Poaceae family have been revealed over the years as important regulators of the responses to various biotic stresses. This chapter provides significant insights into the key TF families like WRKY, NAC, MYB, AP2/ERF, and bZIP that are known to have important functions in gene regulation of plant in response to various biotic stresses, and their potential contribution in the development and improvement of biotic stress-tolerance in sugarcane.