Asthma, and severe asthma, in particular, is increasingly recognized as a heterogeneous disease. While traditional views of asthma have centered around a childhood onset disease with an allergic component, several large scale network studies are now confirming that severe asthma can present in multiple different ways, only 30–50% of which meet traditional childhood onset allergic criteria. To understand the different groups better, initial studies have attempted to define phenotypes of severe asthma. A phenotype is defined as the integration of different characteristics that are the product of the interaction of the patient's genes with the environment. Both clinical and statistical approaches have identified at least 3–5 phenotypes of severe asthma. However, these phenotypes, in isolation, do not identify the immunopathology that makes these clinical phenotypes distinct or identifies a target population for a specific approach to therapy. As biological characteristics are identified, phenotypes should continue to evolve towards asthma endotypes. The identification of these endotypes, either by matching biology, genetics and therapeutic responses to therapy with clinically or statistically defined phenotypes or through unbiased genetic and genomic approaches, remains limited. Moving forward, this integration of genetics, biology and clinical characteristics should substantially enhance our ability to effectively treat complex heterogeneous diseases, such as severe asthma.