Sugarcane (Saccharum officinarum) is a critical global crop, primarily cultivated for sugar and ethanol production, and its effective management is vital for optimal yields. Weeds are a significant biotic stressor in sugarcane farming, competing for resources and causing substantial yield losses. While traditional hand weeding has been largely replaced by mechanical control, the high-energy demands and associated environmental concerns of mechanical methods have led to the widespread adoption of chemical herbicides. Long-term reliance on broad-spectrum herbicide weed control has led to resistance evolution in weeds in sugarcane fields. Given these challenges, breeding herbicide-tolerant sugarcane varieties is becoming increasingly important. Sugarcane’s polyploid nature, long breeding cycles, and limited genetic diversity pose significant barriers to improving herbicide tolerance through conventional breeding. However, advancements in genetic engineering and gene editing techniques, such as CRISPR-Cas9, promise to enhance herbicide resistance in sugarcane. This chapter reviews the current state of herbicide tolerance breeding in sugarcane, discussing biochemical mechanisms of herbicide action, conventional and molecular breeding strategies, and the potential of gene editing to develop herbicide-tolerant varieties. Understanding these methodologies is essential for navigating the future of herbicide use in sugarcane farming and achieving sustainable, high-yield production in the face of evolving agricultural challenges.