Lateral Spreading Tumors (LSTs) are a type of non-polypoid lesion known for their flat morphology, which often leads to them going undetected. However, especially nongranular (NG) LSTs have the potential for malignant transformation. Recent advances in endoscopic technologies have improved the detection of these lesions. Despite growing research interest in their role in colorectal cancer (CRC) development, a comprehensive molecular characterization of LSTs is still lacking. The aim of this review is to highlight the current knowledge of the molecular characteristics of LSTs, that may help in determining whether LSTs can be prognostic indicators and identifying cases where they may rapidly progress to CRC through characteristic molecular pathways. From a mutational point of view, LSTs seem to be more closely associated with inflammatory bowel diseases (IBDs) than with polypoid lesions. Nonetheless, they have peculiar epigenetic and genetic traits, which set them apart from other adenomas or bowel diseases. Elucidating their role in CRC development would provide benefits for their classification and management, by enhancing clinical surveillance strategies for patients diagnosed with these lesions in order to improve the efficient prevention of colorectal cancer.