Targeted delivery of cancer therapeutics has shown significant progress over the past few decades, but only 15 passively targeted nanocarriers (NCs) have been approved for clinical use, with none of the actively targeted NCs advancing past clinical trials. This review discusses the challenges and reasons behind the limited clinical success of targeted delivery approaches. Key challenges include physiological barriers such as tumor penetration, heterogeneity, hypoxia, and endosomal escape, as well as regulatory and manufacturing hurdles. Passively targeted NCs rely on the enhanced permeability and retention (EPR) effect, which allows NCs to accumulate in tumors due to leaky vasculature and defective lymphatic drainage. However, only a small percentage of these NCs accumulate in high-EPR tumors. Active targeting strategies involve using ligands on NC surfaces to target specific receptors on diseased cells, but these strategies face challenges such as endosomal escape, immune recognition, and the need for complex manufacturing processes. The development of actively targeted NCs requires careful consideration of physicochemical properties, targeting ligand density, and the design of efficient delivery systems. Stimuli-responsive NCs that can release therapeutics in response to specific microenvironments are promising but face challenges in scalability and biocompatibility. Local delivery of therapeutics directly to the tumor site is an attractive strategy for overcoming physiological barriers, but it is limited by the inability to target metastases. Regulatory and industry barriers, including the need for good laboratory practices (GLP) and the complexity of NCs, also pose significant challenges to clinical translation. Despite these challenges, ongoing research and development of NCs offer promising opportunities for improving cancer treatment outcomes.Targeted delivery of cancer therapeutics has shown significant progress over the past few decades, but only 15 passively targeted nanocarriers (NCs) have been approved for clinical use, with none of the actively targeted NCs advancing past clinical trials. This review discusses the challenges and reasons behind the limited clinical success of targeted delivery approaches. Key challenges include physiological barriers such as tumor penetration, heterogeneity, hypoxia, and endosomal escape, as well as regulatory and manufacturing hurdles. Passively targeted NCs rely on the enhanced permeability and retention (EPR) effect, which allows NCs to accumulate in tumors due to leaky vasculature and defective lymphatic drainage. However, only a small percentage of these NCs accumulate in high-EPR tumors. Active targeting strategies involve using ligands on NC surfaces to target specific receptors on diseased cells, but these strategies face challenges such as endosomal escape, immune recognition, and the need for complex manufacturing processes. The development of actively targeted NCs requires careful consideration of physicochemical properties, targeting ligand density, and the design of efficient delivery systems. Stimuli-responsive NCs that can release therapeutics in response to specific microenvironments are promising but face challenges in scalability and biocompatibility. Local delivery of therapeutics directly to the tumor site is an attractive strategy for overcoming physiological barriers, but it is limited by the inability to target metastases. Regulatory and industry barriers, including the need for good laboratory practices (GLP) and the complexity of NCs, also pose significant challenges to clinical translation. Despite these challenges, ongoing research and development of NCs offer promising opportunities for improving cancer treatment outcomes.