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Asthma is a heterogeneous chronic inflammatory disease of the airways. The most prevalent form is atopic asthma, which is initiated by the exposure to (inhaled) allergens. Intermittent attacks of breathlessness, airways hyperresponsiveness, wheezing, coughing, and resultant allergen-specific immune responses characterize the disease. Nociceptin/OFQ-NOP receptor system is able to combine anti-hyperresponsiveness and immunomodulatory actions. In particular, N/OFQ is able to inhibit airways microvascular leakage and bronchoconstriction through a presynaptic and non-opioid mechanism of action that blocks tachykinin release. Moreover, it also acts on allergenic sensitization because it is able to modulate the immune response that triggers the development of airway hyperresponsiveness through an interaction on cell membranes of dendritic cells (DCs) that are generally responsible to start and sustain allergic T helper 2 (TH2)-cell responses to inhaled allergens in asthma. In asthmatic patients, sputum showed elevated N/OFQ levels that are related to increased eosinophil counts. The addition of exogenous N/OFQ in sputum obtained from patients with severe asthma attenuated eosinophils migration and release of inflammatory mediators. These observations confirmed that elevated endogenous N/OFQ levels in asthmatic sputum were lower than the ones required to exert beneficial effects, suggesting that supplementation with exogenous N/OFQ may need. In conclusion, the innovative role of N/OFQ in counteracting airways inflammation/hyperresponsiveness opens new potential targets/strategies in asthma treatment.