Male sterility is widespread in angiosperms and is recognized as the failure of a plant to produce viable or functional pollen grains, male gametes and anthers. The development of ideal stable male-sterile lines is an adventurous and challenging task and is instrumental in expediting hybrid breeding programmes in vegetable crops. Lettuce is the number one leafy salad vegetable, and its production is limited by climate change events. The development of hybrids with wider adaptability and high yield is a promising solution to enhance the productivity of this nutritious crop. In this line, male sterility systems hold great promise and are economical for hybrid breeding of self-pollinated crops like lettuce, where the flower structure is composite in nature. The genic male sterility (GMS) line, under the genetic control of the single recessive gene ms-S, has been utilized in lettuce breeding, and linked sequence characterized amplified region (SCAR) markers have been identified. But the process of development of male-sterile lines is slow, and in this context, novel breeding tools like clustered regularly interspaced palindromic repeats-CRISPR-associated protein 9 (CRISPR/Cas9) can be instrumental for speeding up the hybrid breeding programme in leafy vegetable crops, including lettuce. This chapter highlights the current status of male sterility systems in leafy vegetables with a focus on lettuce. The scope of novel genome editing tools in generating male-sterile mutants has been described to expedite the hybrid breeding of lettuce.