Over recent years, advancements in nanomedicine have allowed new approaches to diagnose and treat tumors. Nano drug delivery systems exploit the enhanced permeability and retention (EPR) effect and enter the tumor tissue's interstitial space. However, tumor barriers play a crucial role, and cause inefficient EPR or the homing effect. Mounting evidence supports the hypothesis that the components of the tumor microenvironment, such as the extracellular matrix, and cellular and physiological components collectively or cooperatively hinder entry and distribution of drugs, and therefore, limit the theragnostic applications of cancer nanomedicine. This abnormal tumor microenvironment plays a pivotal role in cancer nanomedicine and was recently recognized as a promising target for improving nano-drug delivery and their therapeutic outcomes. Strategies like passive or active targeting, stimuli-triggered nanocarriers, and the modulation of immune components have shown promising results in achieving anticancer efficacy. The present review focuses on the tumor microenvironment and nanoparticle-based strategies (polymeric, inorganic and organic nanoparticles) for intruding the tumor barrier and improving therapeutic effects.