Abstract: The tumor microenvironment (TME), characterized by its distinct inflammatory profile, acidic pH levels, and hypoxic conditions, holds a pivotal position in regulating tumor behavior, thereby rendering it paramount for devising effective therapeutic strategies. Nanocarriers specifically designed to target the TME have emerged as promising agents in oncology treatment paradigms, attributing to their heightened targeting specificity, extensive drug loading capacity, and versatility in executing multifaceted therapeutic interventions. However, traditional nanoparticles design based on passive targeting are gradually proving to be difficult to achieve efficient delivery. How to design targeting carriers based on the tumor microenvironment and how to achieve rapid and precise delivery by modifying ligands, which here listed as pivotal and challenging issues in nanomedicine development. This comprehensive review delves into the intricate designs of drug delivery systems tailored for the TME, which exhibit specific and microenvironment-responsive characteristics. It explores both passive and active targeting methodologies, highlighting the challenges posed by the tumor's enhanced permeability and retention effects, along with the potential of ligand-mediated active targeting. Furthermore, it applauds the advancements in innovative treatments that capitalize on the unique attributes of the TME to enhance drug efficacy and optimize patient outcomes. Our novelty focused on a comprehensive summary of recent studies concerning nanocarriers that target the tumor microenvironment, proposes future directions and conceptual frameworks for the development of targeting ligands, examines potential targets within the tumor microenvironment, and concludes with a perspective on strategic approaches pertaining to the engineering of pertinent nanocarriers.