Normal cells (orange), often after long-term exposure to carcinogens, can obtain changes in key molecular pathways and cause uncontrolled proliferation (light purple) leading to a premalignant or precancerous lesion. Normal cells (orange), often after long-term exposure to carcinogens, can obtain changes in key molecular pathways and cause uncontrolled proliferation (light purple) leading to a premalignant or precancerous lesion. After accumulating additional alterations, cells are able to invade surrounding tissues forming a tumor (dark purple); however, in some cases, precancerous lesions naturally regress as marked by the bidirectional arrows. Changes in the microenvironment may also contribute to a lesion's progression or regression. For example, functional immune cells (blue) with the capability of recognizing and destroying abnormal cells may eventually be repressed (black) by activation of immune checkpoints. We propose the “Pre-Cancer Genome Atlas (PCGA)” initiative to comprehensively profile molecular alterations in premalignant lesions and the surrounding microenvironment throughout the stages of progression towards or regression from invasive cancer. In tissues that can be accessed via relatively noninvasive procedures, premalignant lesions can be sampled longitudinally to better understand the relationship between molecular alterations, progression/regression, and other clinical outcomes. In tissues that are difficult to access, these premalignant lesions can be cross-sectionally sampled in regions surrounding resected tumors to gain insights about the evolutionary history of themalignant cells. By identifying and understanding the initial events that drive initiation, progression, regression and invasion, we will advance early detection biomarkers and identify effective intervention strategies to reduce the number of individuals with aggressive advanced stage disease. Joshua D. Campbell et al. Cancer Prev Res 2016;9:119-124 ©2016 by American Association for Cancer Research