Lettuce is a vegetable planted in temperate areas worldwide. As a crop, lettuce faces many challenges from biotic stressors, which constitute a top priority for the breeding industry. Diseases and insects can diminish yield due to cosmetic damage to the foliage, which is the consumable part of the plant. Abiotic stressors, such as low calcium in the soil, also significantly affect the crop. This chapter explores advances in lettuce breeding and genetic studies; the latter of which has provided information on several important traits related to both biotic and abiotic stressors, with data available to breeders worldwide. Sections are included on breeding priorities for biotic stressors in lettuce (foliar, soil-borne and other diseases), and also on important insect pests in lettuce. The abiotic stressors such as heat, drought, salinity and tipburn in lettuce are also covered. The chapter concludes with sections on other important traits for the improvement of lettuce and lettuce breeding.