Our work focuses using genomic approaches to understand two important areas of human disease: tumor microenvironmental stresses and erythrocyte microRNAs. We are using a gene expression approach to understanding how cancer cells respond to their microenvironmental stresses, such as oxygen depletion (hypoxia), high lactate and extracellular acidosis (lactic acidosis), and glucose/energy deprivation. We have defined these individual stresses in vitro to generate portable expression signatures to link with in vivo gene expression of human cancers. The prognostic molecular signatures of human cancers are also linked to ex vivo experimental cell culture models for mechanistic studies. In addition, we have also used latent factor models and in vivo cancer data to further dissect gene signatures into components or sub-signatures which better represent the complexity of human cancers. We have identified many segmental aneuploidies associated with tumor microenvironmental stresses and may reflect the selective pressure. Similarly, we also discovered abundant, diverse microRNAs in human erythrocytes. While previous analyses of erythrocyte diseases has focused on DNA polymorphisms, such studies have failed to directly analyze erythrocytes, which are the most directly affected tissue. Discovery of erythrocyte microRNAs has allowed us to similar genomic approaches to analyze erythrocyte microRNA composition in the context of sickle cell diseases. For example, we found the microRNA dysregulation in sickle erythrocytes associated with anemia heterogeneity offer mechanistic insights of sickle cell disease. We are also trying to understand how the erythrocyte microRNAs can inform us of the processes in many human diseases affecting erythrocytes.