Imbalance in the tissue microenvironment is the main obstacle to drug delivery and distribution in the human body. Before penetrating the pathological tissue microenvironment to the target site, therapeutic agents are usually accompanied by three consumption steps: the first step is tissue physical barriers for prevention of their penetration, the second step is inactivation of them by biological molecules, and the third step is a cytoprotective mechanism for preventing them from functioning on specific subcellular organelles. However, recent studies in drug-hindering mainly focus on normal physiological rather than pathological microenvironment, and the repair of damaged physiological barriers is also rarely discussed. Actually, both the modulation of pathological barriers and the repair of damaged physiological barriers are essential in the disease treatment and the homeostasis maintenance. In this review, we present an overview describing the latest advances in the generality of these pathological barriers and barrier-modulated nanomedicine. Overall, this review holds considerable significance for guiding the design of nanomedicine to increase drug efficacy in the future.