The article reviews the progress and challenges in the development of targeted delivery approaches for cancer therapeutics. While passively targeted nanocarriers (NCs) have shown some success in clinical use, actively targeted NCs have not advanced beyond clinical trials. The review highlights the physiological barriers that limit the efficacy of NCs, such as tumor penetration, heterogeneity, hypoxia, and endosomal escape. It also discusses the complex design and manufacturing processes of actively targeted NCs, which add to their clinical translation challenges. The authors propose criteria and considerations for developing novel actively targeted NCs, emphasizing the importance of understanding nano-bio interactions and the need for companion diagnostic imaging technologies. They suggest that combining local delivery with other targeting strategies, such as active targeting and stimuli-responsive NCs, could improve therapeutic outcomes. Additionally, regulatory and industry barriers, including the rarity of good laboratory practices (GLP) conditions and the need for innovative regulatory tools, are discussed as significant hurdles to the clinical translation of NC-based therapeutics.The article reviews the progress and challenges in the development of targeted delivery approaches for cancer therapeutics. While passively targeted nanocarriers (NCs) have shown some success in clinical use, actively targeted NCs have not advanced beyond clinical trials. The review highlights the physiological barriers that limit the efficacy of NCs, such as tumor penetration, heterogeneity, hypoxia, and endosomal escape. It also discusses the complex design and manufacturing processes of actively targeted NCs, which add to their clinical translation challenges. The authors propose criteria and considerations for developing novel actively targeted NCs, emphasizing the importance of understanding nano-bio interactions and the need for companion diagnostic imaging technologies. They suggest that combining local delivery with other targeting strategies, such as active targeting and stimuli-responsive NCs, could improve therapeutic outcomes. Additionally, regulatory and industry barriers, including the rarity of good laboratory practices (GLP) conditions and the need for innovative regulatory tools, are discussed as significant hurdles to the clinical translation of NC-based therapeutics.