The modern cultivated tomato (Solanum lycopersicum) was domesticated from Solanum pimpinellifolium native to the Andes Mountains of South America through a “two-step domestication” process. It was introduced to Europe in the 16th century and later widely cultivated worldwide. Since the late 19th century, breeders, guided by modern genetics, breeding science, and statistical theory, have improved tomatoes into an important fruit and vegetable crop that serves both fresh consumption and processing needs, satisfying diverse consumer demands. Over the past three decades, advancements in modern crop molecular breeding technologies, represented by molecular marker technology, genome sequencing, and genome editing, have significantly transformed tomato breeding paradigms. This article reviews the research progress in the field of tomato molecular breeding, encompassing genome sequencing of germplasm resources, the identification of functional genes for agronomic traits, and the development of key molecular breeding technologies. Based on these advancements, we also discuss the major challenges and perspectives in this field.