Tomatoes, a major food source for humans, accumulate a variety of secondary metabolites including phenolic compounds, phytoalexins, protease inhibitors, and glycoalkaloids. These metabolites protect against adverse effects of hosts of predators including fungi, bacteria, viruses, and insects. Because glycoalkaloids are reported to be involved in host-plant resistance, on the one hand, and to have a variety of pharmacological and nutritional properties in animals and humans, on the other, a need exists to develop a better understanding of the role of these compounds both in the plant and in the diet. To contribute to this effort, this integrated review presents data on the history, composition, and nutrition of tomatoes, with special focus on the assessment of the chemistry, analysis, composition, nutrition, microbiology, and pharmacology of the tomato glycoalkaloids comprising alpha-tomatine and dehydrotomatine; their content in different parts of the tomato plant, in processed tomato products, and in wild and transgenic tomatoes; their biosynthesis, inheritance, metabolism, and catabolism; plant-microbe relationships with fungi, bacteria, viruses, insects, and worms; interactions with ergosterol and cholesterol; disruption of cell membranes; tomatine-induced tomatinases, pantothenate synthetase, steroid hydroxylases, and cytokines; and inhibition of acetylcholinesterase. Also covered are tomato-human pathogen relationships and tomatine-induced lowering of plasma cholesterol and triglycerides and enhancement of the immune system. Further research needs in each of these areas are suggested. The overlapping aspects are discussed in terms of general concepts for a better understanding of the impact of tomato glycoalkaloids in the plant in general and in food in particular. Such an understanding can lead to the creation of improved tomatoes and to improved practices on the farm and in the consumption of tomatoes.