Aberrant crypt foci (ACF) in colorectal mucosa are the earliest known morphological precursors to colorectal cancer and can be subclassified as dysplastic, heteroplastic (non-dysplastic), and mixed types. Serrated adenoma (SA) is a polyp with serrated architecture and dysplasia, and can be subclassified as traditional SA or sessile SA. Sessile SA is thought to be preneoplastic and differs from most lesions in the traditional SA category because of their flat morphology and general lack of cytological dysplasia. Serrated polyps include hyperplastic polyps (HP), SA, and admixed hyperplastic-adenomatous polyps and are considered a morphological continuum encompassing heteroplastic ACF, HP, admixed hyperplastic-adenomatous polyps, and SA. Recent studies have uncovered other developmental pathways including a heteroplastic ACF-HP/SA-carcinoma sequence and a heteroplastic ACF-adenoma-carcinoma sequence. Heteroplastic ACF histopathologically resemble HP and SA. Sporadic HP are usually present in the left colon, are small, and are considered benign. However, adenocarcinoma arising in the setting of colorectal HP or SA, especially in patients with hyperplastic polyposis, has been described. The relationship between heteroplastic ACF, HP, and colorectal cancer is less certain than that of dysplastic ACF. Here, we discuss the current understanding of genetic and epigenetic alterations in the development of colorectal cancer. Our goal is to provide a conceptual framework for understanding the heteroplastic ACF-HP/SA-carcinoma sequence. (1) Most colorectal cancers (CRC) develop from adenomatous polyps (tubular adenoma) and show morphological and genetic progression through an adenomacarcinoma sequence, even in hereditary colorectal cancer syndromes. (2)(3)(4) Sporadic HP are usually present in the left colon, are small, and are generally regarded as harmless lesions with no potential for malignancy.(5,6) However, adenocarcinoma arising in the setting of colorectal HP or serrated adenomas (SA), especially in patients with hyperplastic polyposis (HPP), which is characterized by the presence of numerous HP or large HP, have been described.(7-11) Indeed, patients with HPP have an increased risk of CRC.(11-18) Serrated polyps (SP) include HP, SA, and admixed hyperplastic-adenomatous polyps (AHAP), (19,20) and are considered a morphological continuum encompassing non-dysplastic (heteroplastic) aberrant crypt foci (ACF), HP, AHAP, and SA. (21) SA are composed of dysplastic epithelium but with the sawtooth configuration that is typical of HP. (20) SA are subclassified as traditional SA and sessile SA. (22,23) Sessile SA is thought to be preneoplastic and differs from most lesions in the traditional SA category because of its flat morphology and general lack of cytological dysplasia. (22,23) The incidence of SA is reported to be 0.8-4.9% of colorectal tumors. (24,25) In addition, the incidence of carcinoma in SA is reported to be 1.5-19.2%, which is equal to or lower than the incidence in tubular adenoma.Recent studies have proposed ...