In both men and women, colorectal cancer is the third most commonly diagnosed cancer and the third leading cause of cancer death in the United States. These cancers harbor up to 90 distinct mutations. Recent advances in sequencing have led to tumor profiling in the clinic with the goal of identifying mutations that are targetable using newly developed chemotherapeutic agents. Critical to this more personalized approach to treatment is the realization that tumors can have a polyclonal structure and that each clone within the tumor is likely to have a different mutation profile. Therefore, the effectiveness of a targeted agent that eliminates a specific clone with a particular oncogenic mutation will depend on the relationship among the clones within the tumor. If an initiated progenitor recruits others through paracrine oncogenic signaling, the elimination of the initiated progenitor and its descendants would likely elicit a complete response at least during the early stages of tumorigenesis, as the recruited clone(s) would likely be reliant on the original clone. As a polyclonal tumor progresses, it is unclear whether the relationship among clones changes. Polyclonality might still be necessary or at least beneficial to the tumor. In this context, targeting a specific clone would again elicit a significant response. Alternatively, the different clones within a tumor might rapidly diverge as additional mutations accumulate. If clones do diverge, interactions among clones might no longer be necessary. In this context, elimination of the initial progenitor and its descendants would elicit only a partial response at best, so each and every clone would need to be targeted to elicit a complete response. Our goal is to develop an understanding of the mechanism of recruitment to better understand how polyclonal tumors form, compare the mutation profile of monoclonal and polyclonal polyps, determine how common mutations affect the clonal structure of a tumor, test how targeting a specific clone within a tumor affects response to chemotherapy, and determine whether polyclonality is a prognosticator of polyp growth, cancer recurrence and/or survival in the clinic. These goals are being met using a unique experimental platform that we have developed in the past five years and by examining archived human samples, including colorectal polyps that were monitored for an average of two to three years by serial CT colonography prior to removal.