Cystic fibrosis (CF), a lethal genetic disease, is characterized by substantial clinical heterogeneity. Work over the past decade has established that much of the variation is genetically conferred, and recent studies have begun to identify chromosomal locations that identify specific genes as contributing to this variation. Transcriptomic and proteomic data, sampling hundreds and thousands of genes and their products, point to pathways that are altered in the cells and tissues of CF patients. Genetic studies have examined more than half a million polymorphic sites and have identified regions, and probably genes, that contribute to the clinical heterogeneity. The combination of these approaches has great potential because genetic profiling identifies putative disease-modifying processes, and transcript and protein profiling is shedding light on the biology involved. Such studies are providing new insights into the disease, such as altered apoptotic responses, oxidative stress dysregulation, and neuronal involvement, all of which may open new therapeutic avenues to exploration.