Nanoparticles (NPs) have been extensively researched for targeted diagnostic imaging and drug delivery, yet their clinical translation remains limited, with only a few achieving Food and Drug Administration approval. This limited success is primarily due to challenges in achieving precise organ- or tissue-specific targeting, which arise from off-target tissue accumulation and suboptimal clearance profiles. Herein we examine the critical role of physicochemical properties, including size, surface charge, shape, elasticity, hardness, and density, in governing the biodistribution, targetability, and clearance of NPs. We highlight recent advancements in engineering NPs for targeted imaging and drug delivery, showcasing both significant progress and the remaining challenges in the field of nanomedicine. Additionally, we discuss emerging tools and technologies that are being developed to address these challenges. Based on recent insights from materials science, biomedical engineering, computational biology, and clinical research, we propose key design considerations for next-generation nanomedicines with enhanced organ selectivity.