Abstract Merging the social science concept of diaspora with ecological and population sciences concepts can inform the cancer field to understand the biology of tumorigenesis and metastasis and inspire new ideas for therapy. Together, cancer cells and host cells, interacting within their habitat, create an ecosystem. This ecosystem, in turn, exists within a larger environment (the host patient as biosphere). Cancer cells escape their confinement of their original habitat in the primary tumor, likely forced out by ecological changes in their home niche. A diaspora is the scattering of people away from an established homeland. To date, “diaspora” has been a uniquely human term utilized by social scientists, however, the application of the diaspora concept to metastasis may yield new biological insights as well as therapeutic paradigms. The diaspora paradigm takes into account and models several variables: the quality of the primary tumor microenvironment, the fitness of individual cancer cell migrants as well as migrant populations, the rate of bidirectional migration of cancer and host cells between cancer sites, and the quality of the target microenvironments to establish metastatic sites. Once seeded to a new site, diaspora populations do not assimilate into the new environment, they try “recapitulate” their homeland. Niche construction is the process in which an organism alters its own (and consequently, other species) environment, usually in a manner that increases its chances of survival. This creates a feedback relationship between natural selection and niche-construction: when organisms affect their environment, that change can then cause a shift in what traits are being naturally selected for. The effect of niche construction is especially pronounced in situations where environmental alterations persist for several generations, introducing the evolutionary role of ecological inheritance. Ecological scientific principles can be applied to the cancer diaspora to develop new therapeutic strategies (ecotherapy). It is easier to drain the swamp that the cancer cells created than swat a million cancer cell mosquitos. Alternatively, ecological traps, habitats that lead to the extinction of a species, could be developed to attract cancer cells to a place where they can be better exposed to treatments or to cells of the immune system for improved antigen presentation. Targeting the microenvironment in addition to the cancer cells themselves should improve therapeutic outcomes. Citation Format: Kenneth J. Pienta. Of niche construction and loss of homeostasis: New insights into the cancer diaspora. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr IA21. doi:10.1158/1538-7445.CHTME14-IA21