Genomics has already begun to foster a more personalized, predictive and preventive medicine. In particular, the rapid increases in high-throughput sequencing and our ability to interrogate numerous molecular mechanisms at a genome-wide scale has informed the understanding, diagnosis, and treatment of genetic diseases. In my presentation, I will demonstrate how work in my laboratory bridges diverse domains of genome science, from research aimed at gaining a fundamental understanding of the structure and function of genomes, to the application of these insights towards improving our understanding of diseases and advancing the effectiveness of treatments. We use multiple model organisms as platforms for developing technologies that enable us to dissect the genetics underlying complex traits, aiming at a systematic understanding of the molecular events that lead from genotype to phenotype. We work extensively on functional and mechanistic characterizations of transcription, the first manifestation of genetic variation; in addition, we study multiple diseases in model systems in order to profile the underlying networks and predict effective therapeutic strategies. Our overall goal is to establish approaches and discover biological principles that will enable the prediction and prevention of genetic diseases.