Next Generation Cancer Models (NGCMs) Most 2-dimentional cancer cell lines currently used to study the etiology of cancer, e.g. mechanism, treatment response, etc. inadequately model its genetic, epigenetic, and phenotypic complexity. Many lack molecular characterization of the original tumor’s genome, epigenome and transcriptome (and the case-matched normal DNA) as well as the clinical presentation, treatment, and outcome data. In addition, cell lines from certain subtypes (defined by pathology or molecular features) or populations, as well as rare and pediatric cancers, are underrepresented or not available. Reasonably robust protocols to establish the NGCMs from a number of tumor subtypes have been developed over the past several years. Organoid, conditionally reprogrammed cells (CRC), modified versions of those methods, and unique media formulations can be used to establish models, which appear to address current gaps in cancer models. Some protocols even allow co-culture of tumor and stroma tissues. Organoid culture methods were first created using stem cells from the mouse small intestine. The models usually consist of two or more cell types and develop structures that resemble in vivo organs, but lack innervation, blood supply, and mesenchyme. These three-dimensional structures are grown from epithelial stem cells and are amenable to expansion in culture under appropriate conditions. Cultures are grown in exogenous extracellular matrix using media that contain components that drive cell proliferation and differentiation, such as Noggin, R-spondin, Wnt, and epidermal growth factor. The method has been adapted to propagate other cell and tumor subtypes for many months which appear to be representative of the original tumors. Research is ongoing to determine if the NGCMs are immortal, genomically stable etc. CRC methodology was pioneered using human keratinocytes and subsequently expanded to other epithelial cell types. Propagation of primary or tumor human cells requires Rho kinase inhibitor and irradiated mouse fibroblast feeder cells. The CRCs proliferate indefinitely as stem-like cells but appear to maintain the ability to differentiate. Although they are typically cultured as monolayers, CRCs can also develop into organ-like three-dimensional structures when grown in a supporting matrix. New media formulations have also been very successful in establishing models from tumor types historically difficult to propagate in culture. As opposed to standard culture media that contain on average 40-50 ingredients, these new media have over 80 components. For example, using complex medium to establish cell lines from a diverse array of ovarian tumors, results in cultures that retain most of the genomic and molecular features of the tissue from which they originated. The NCI Office of Cancer Genomics (OCG), Center for Cancer Genomics, together with international institutions, established a consortium, the Human Cancer Models Initiative (HCMI) whole...