Targeted polymeric therapeutic nanoparticles (NPs) have emerged as a promising class of therapeutics with the potential to significantly enhance drug safety and efficacy. These NPs are engineered to navigate the complex in vivo environment, incorporating functionalities for target specificity, controlled drug release, and optimal pharmacological properties. Unlike first-generation NPs, which primarily facilitated drug formulation, targeted polymeric NPs are designed to deliver drugs to specific sites, improving therapeutic outcomes. The integration of multifunctional NPs with optimally designed drugs allows for improved clinical outcomes that may not be achievable with conventional drug administration. This review discusses the design, development, and clinical translation of targeted polymeric NPs, highlighting their potential to become a highly differentiated class of therapeutics distinct from traditional drugs. Key challenges include optimizing NP design, ensuring reproducible synthesis, and addressing biophysicochemical properties that affect clinical performance. The review also highlights recent examples of targeted polymeric NPs, such as SP1049C, NK911, and Genexol-PM, which have shown promise in clinical trials. Additionally, the review explores the mechanisms of passive and active targeting, emphasizing the role of EPR effect in tumour accumulation and the limitations of passive targeting. Active targeting involves the use of affinity ligands to direct NPs to specific antigens, enhancing cellular uptake and therapeutic efficacy. The clinical translation of targeted polymeric NPs remains a challenge, but ongoing research and development are paving the way for their successful application in various therapeutic areas. The review underscores the importance of continued innovation in NP design and development to overcome existing limitations and realize the full potential of targeted polymeric NPs in medicine.Targeted polymeric therapeutic nanoparticles (NPs) have emerged as a promising class of therapeutics with the potential to significantly enhance drug safety and efficacy. These NPs are engineered to navigate the complex in vivo environment, incorporating functionalities for target specificity, controlled drug release, and optimal pharmacological properties. Unlike first-generation NPs, which primarily facilitated drug formulation, targeted polymeric NPs are designed to deliver drugs to specific sites, improving therapeutic outcomes. The integration of multifunctional NPs with optimally designed drugs allows for improved clinical outcomes that may not be achievable with conventional drug administration. This review discusses the design, development, and clinical translation of targeted polymeric NPs, highlighting their potential to become a highly differentiated class of therapeutics distinct from traditional drugs. Key challenges include optimizing NP design, ensuring reproducible synthesis, and addressing biophysicochemical properties that affect clinical performance. The review also highlights recent examples of targeted polymeric NPs, such as SP1049C, NK911, and Genexol-PM, which have shown promise in clinical trials. Additionally, the review explores the mechanisms of passive and active targeting, emphasizing the role of EPR effect in tumour accumulation and the limitations of passive targeting. Active targeting involves the use of affinity ligands to direct NPs to specific antigens, enhancing cellular uptake and therapeutic efficacy. The clinical translation of targeted polymeric NPs remains a challenge, but ongoing research and development are paving the way for their successful application in various therapeutic areas. The review underscores the importance of continued innovation in NP design and development to overcome existing limitations and realize the full potential of targeted polymeric NPs in medicine.