The advent of antibody-drug conjugates (ADCs) aims to transform the therapeutic landscape of advanced non-small cell lung cancer (NSCLC). The distinctive architecture of ADCs enables the targeted delivery of highly potent cytotoxic payloads directly to cancer cells that express the molecular target specified by their monoclonal antibody component. This precision targeting stems from the notion that ADCs may be highly effective therapeutic agents, particularly for treating NSCLC tumors harboring actionable genomic alterations (AGAs). In this context, ADCs can be categorized into two main types: Biomarker-selected ADCs, which require the tumor to present a specific pattern of the protein targeted by the ADC (e.g., MET overexpression, HER2 overexpression or mutation) and formally requiring biomarker testing, and biomarker-agnostic ADCs, which target proteins that are broadly expressed in lung cancer cells (e.g., anti-TROP2 or HER.3 ADCs), and hence no pre-testing is required. The cytotoxic payload is expected to be delivered in high concentration in the cancer cells carrying the corresponding target of interest, while minimizing off-target toxicity. In this review, we describe available evidence regarding the efficacy and safety of ADCs in NSCLC harboring AGAs. We also discuss the challenges with respect to appropriate biomarker selection, dose optimization, treatment duration, and optimization of the structural design of ADC components to maximize efficacy while minimizing off-target toxicity. Finally, addressing cost-effectiveness concerns remains critical for their successful adoption within healthcare systems.