Asthma is a chronic airway disease consisting of usually variable airflow limitation and bronchial hyperresponsiveness. Many different phenotypes characterize the clinical expression of asthma, determined by heterogeneous inflammatory patterns driven by distinct cellular and molecular mechanisms known as endotypes. Inside the complex framework of asthma pathobiology, several molecules such as immunoglobulins E (IgE), pro-inflammatory cytokines and their receptors can be targeted by present and future biological treatments of severe asthma. Within this context, already registered monoclonal antibodies including omalizumab, mepolizumab, reslizumab, benralizumab and dupilumab may interfere at various levels with the pathogenic pathways responsible for type-2 airway inflammation. In particular, these drugs target IgE (omalizumab), IL-5 (mepolizumab and reslizumab), IL-5 receptor (benralizumab) and IL-4/IL-13 receptors (dupilumab), respectively. Moreover, other biological therapies are under evaluation in premarketing trials, mainly aimed to assess the efficacy and safety of monoclonal antibodies directed against innate cytokines such as IL-33 and thymic stromal lymphopoietin (TSLP). Among current and perspective therapeutic approaches, clinicians can choose phenotype/endotype-driven tailored treatments, able to pursue an effective control of difficult to treat type-2 asthma.