The molecular alterations associated with early pathological steps preceding the development of invasive carcinoma have not been well characterized. A Pre-Cancer Genome Atlas (PCGA) is needed both to support the collection and molecular profiling (circus plot) of premalignant lesions (purple cells) to identify the sequence of initial driver events that cause normal cells (orange cells) to acquire cancer hallmarks that enable lesions (purple cells) to progress to fully invasive carcinoma, including the critical “additional genomic events” (e.g., checkpoint/tumor suppressor loss or other co-activating event) that transform premalignancy (purple cells in the fourth circle to the right) to cancer (far right). In addition to defining the sequence of genomic driving events in specific neoplastic sites, characterizing the premalignant inflammatory microenvironment, including the contribution of the stroma and immune cell (blue) regulation, will provide a better understanding of the selective forces that determine which molecular drivers give an evolutionary advantage to drive premalignant lesions to become invasive cancer. This figure is modified in part from Campbell et al. (21).