Despite advances in asthma initiatives, there continues to be a large population of patients with severe asthma whose condition remains uncontrolled despite the use of inhaled combination corticosteroids and long-acting beta-agonist treatment. For this population, which may include as many as one-third of all patients with asthma, biological therapy is often a treatment consideration in specialist clinics. In contemporary asthma care, and in the scope of this paper, the term “biological agent” indicates the use of a monoclonal antibody. In an attempt to avoid the side effects of oral corticosteroid therapy, specialists often feel obligated to add this therapeutic option. With an anticipated influx of monoclonal antibody therapies soon to come to market, the necessity of appropriately stratifying patients prior to initiating such therapy is of paramount necessity. It is important to recognize that following accepted prescribing criteria does not necessarily equate to anticipated clinical response. Omalizumab provides a prime example in which, based on current prescribing criteria, as many as one-half of the patients who are administered the medication may be poor responders. Postmarket studies of omalizumab suggest that other phenotypic markers such as exhaled fractional nitrous oxide, periostin, and blood eosinophil levels better define predicted response to therapy.