Difficult-to-control asthma is a disease that causes serious exacerbations, near-fatal attacks, frequent hospitalizations, and needs chronic use of high doses of inhaled corticosteroids or daily oral corticosteroid therapy. On the basis of epidemiological studies, the risk factors for serious asthma are: female gender, high BMI, sensitivity to aspirin, gastro esophageal reflux, sinusitis, pneumonia history, and beginning of asthma symptoms in adult late age. It has been found that in severe asthma the inflammatory profile commonly changes with major participation of neutrophils, and evidence of destruction and remodelling. The first step in the care of these patients is an evaluation to determine that asthma is the right diagnosis. A systematic and rigorous evaluation helps to asses adequately the differential diagnoses, the comorbilities and the unusual triggers. The aim of the treatment is to achieve the best results with minimum adverse effects. New immunomodulatory therapies are needed for these patients management.