Lettuce is a popular leafy vegetable and plays an important role in American diet and nutrition. Crisphead lettuce has much lower nutrient content than leaf and romaine types. As the synthesis or absorption of many nutrients is light dependent, the lower nutritional value of crisphead lettuce is due to the enclosure of its leaves in a head structure. In addition to varietal differences, nutritional quality of lettuce may be influenced by environmental factors such as light, temperature, growing season, cultural practices, fertilizer application, and storage conditions. The moisture content of the plant also affects nutrient concentration. Enhancing the nutritional levels of vegetables would improve the nutrient intake without requiring an increase in consumption. Genotypic variation in germplasm suggests that genetic improvement of nutritional value is feasible in lettuce. However, breeding efforts for nutrition are often hampered by the lack of analytical capabilities in most crop improvement programs. Biotechnology has the potential to markedly increase the nutritional value of lettuce. The commercialization of transgenic lettuce may largely depend on progress in transgene expression, public acceptance, economic and marketing challenges, intellectual property issues, and risk assessment.