Severe asthma imposes a significant burden on public health worldwide, mainly due to its morbidity and high cost. The management of severe asthma has dramatically changed in the past few years with the introduction of biologics. Zero exacerbations, zero systemic corticosteroids, better asthma control, and better lung function are the outcomes that the era of biologics has made attainable in a large proportion of severe asthmatics, ending up in a better quality of life. Still, even today, the changes at the tissue level that reflect these outcomes are not that clear. As a chronic inflammatory disease, asthma often involves airway remodeling in its severe forms; endobronchial biopsies may provide critical insights into these tissue-level changes before and after biologic treatment. However, bronchoscopy is an invasive tool for severe asthma, thus limiting its use in daily clinical practice. This review focuses on summarizing the changes that biologics exert in biopsies obtained from severe asthmatics under biological treatment, providing an opportunity to shed light on what really happens there where it is not easy to see, and especially on what does not happen in patients under biologics who fail to respond as expected. Moreover, the armamentarium of biomarkers used for making the proper choice in patients eligible for more than one biologic needs to be enriched. Biopsy-related markers could be an ideal adjunct to the current ones-blood eosinophils, FeNO, and IgE-to assist the clinician to choose the right biologic for the right patient with severe asthma to achieve disease remission.