About two-thirds of global sugar production depends on sugarcane, a major commercial crop in many tropical countries. Sugarcane production is threatened by various diseases caused by fungi, bacteria, phytoplasma and viruses. The severity and occurrence of the diseases depend on various factors, viz., host genotype, the prevalence of the pathotype, soil, temperature, humidity, etc. It is one of the most complex polyploidy crops, wherein the complexity is exacerbated with around 10–13 sets of homologous chromosomes. Hence, deciphering the complete genome of sugarcane remained a herculean task. While pathologists worldwide are constantly working to understand the molecular basis of disease resistance with various sugarcane genotypes and pathogens, breeders continue to improve the genetic makeup and develop commercially superior sugarcane varieties specific to various agro-climatic conditions through conventional breeding approaches. In this context, this chapter highlights the understanding of sugarcane disease resistance with a major focus on two critical diseases, viz., red rot and smut, at the molecular level and presents how the disease resistance in sugarcane can be enhanced from the perspective of sugarcane pathologists.