Tomatoes produce the bioactive compounds lycopene and α-tomatine that are reported to have potential health-promoting effects in animals and humans, but our understanding of the roles of these compounds in the diet is incomplete. Our current knowledge gained from the chemistry and analysis of these compounds in fresh and processed tomatoes and from studies on their bioavailability, bioactivity, and mechanisms of action against cancer cells and other beneficial bioactivities including antibiotic, anti-inflammatory, antioxidative, cardiovascular, and immunostimulating effects in cells, animals, and humans is discussed and interpreted here. Areas for future research are also suggested. The collated information and suggested research might contribute to a better understanding of the agronomical, biochemical, chemical, physiological, molecular, and cellular bases of the health-promoting effects and facilitate and guide further studies needed to optimize the use of lycopene and α-tomatine in pure form and in fresh tomatoes and processed tomato products to help prevent or treat human disease.