Asthma affects over 300 million people worldwide. Most asthmatics are well controlled with inhaled corticosteroids and long-acting beta-agonists; however, a proportion of patients are unresponsive and attain limited disease control. This group represents a considerable healthcare and financial burden, particularly patients who experience frequent exacerbations and require hospital admission. Development of new biological agents and disease biomarkers has provided novel avenues for treatment. These treatments have been highly successful, reducing exacerbations and yielding modest improvements in quality of life and lung function. However, only a proportion of severe asthmatics respond to this targeted treatment, highlighting the heterogeneity of severe asthma. One of the first biological therapies targeted immunoglobulin E (IgE) and demonstrated modest benefit but could only be used in a subgroup of patients. Recent research has shown that treatment aimed at the T helper-2-(Th2)-high pathways and cytokines such as interleukin (IL)-5, IL-4, and IL-13 may also be effective in another partially overlapping subgroup. A blood eosinophil count over a defined threshold (generally ≥300 cells/μl) was a reliable biomarker and identified the majority of responders in this group. Further discovery and validation of biological markers to define asthmatic phenotypes that may benefit from biological treatments remain an area of intense interest and research. We review the latest information pertaining to biological agents and demonstrate how patient responders may potentially be identified for treatment.