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Chronic rhinosinusitis with nasal polyps (CRSwNP) is a heterogeneous inflammatory disorder in which type 2 inflammation predominates but varies in its local organization, clinical context, and downstream tissue effects. Biologics targeting interleukin-4 receptor alpha, immunoglobulin E, the interleukin-5/interleukin-5 receptor axis, and thymic stromal lymphopoietin have expanded treatment options for severe disease and can improve polyp burden, nasal obstruction, olfactory function, quality of life, and corticosteroid- or surgery-related outcomes. However, responses remain variable across patients and clinical domains, and incomplete control may reflect target mismatch, persistent parallel inflammatory pathways, comorbid airway disease, or established tissue remodeling rather than insufficient pathway coverage alone. In this review, we summarize the mechanisms and clinical evidence for current monospecific antibodies and examine biological contexts that may contribute to variable treatment responses, including local IgE activity, microbial and antigenic amplification, nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD), comorbid asthma, and persistent epithelial remodeling. We then discuss biomarkers, multidimensional response assessment, and clinical positioning of biologic therapy before evaluating the rationale, boundaries, molecular design, and current pipeline of dual- and multispecific antibodies. Attention is given to whether broader pathway targeting can provide incremental benefit over optimized monospecific therapy, while maintaining acceptable long-term safety, treatment practicality, and economic value. The future role of multispecific biologics in CRSwNP will depend on rational target pairing, comparative clinical evidence, and improved identification of patients most likely to benefit.