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Uncontrolled, severe asthma remains a significant clinical challenge, affecting a small proportion of asthma patients worldwide. Despite advancements in treatment options, a subset of patients continues to experience frequent exacerbations, uncontrolled symptoms, and impaired quality of life. The advent of biological therapies has revolutionized the management of severe asthma, offering targeted treatments that address specific inflammatory pathways. This review provides a comprehensive overview of the efficacy and response criteria of biological treatments in severe asthma, focusing on clinical, functional, and inflammatory markers used to help in the evaluation of the biologic treatment. Key response criteria include symptom control, reduction in exacerbations, improvement in lung function, and a reduction in or the discontinuation of oral corticosteroids. Biomarkers such as blood eosinophils and exhaled nitric oxide (FeNO) are essential tools in guiding treatment adjustments. Real-world studies underscore the importance of personalized treatment strategies, as variability in response to biological therapies can be significant. The emergence of tools such as the FEOS score and EXACTO questionnaire offer quantitative measures for assessing biological response and guiding clinical decisions. Additionally, predictive factors for better or poorer responses, such as pre-treatment lung function and comorbidities, like obesity and rhinosinusitis, are critical in patient selection. This review highlights the need for ongoing reassessments and potential modifications of therapy in cases of suboptimal response. Practical considerations for switching biological therapies are discussed, emphasizing the importance of tailoring treatments to individual patient profiles and disease phenotypes. With the continued development of personalized medicine, the outlook for patients with severe asthma is improving, selecting specific biomarkers to improve the selection of the biologic treatment.