In this review, we focus on the main crosslinking mechanisms that commonly exist in a plethora of chronic diseases (e.g. fibrosis, cancer, osteoarthritis) and summarize current understandings including the biochemical reaction, the effect on ECM properties, the influence on cellular behaviors, and related studies in disease model establishment. Potential pharmaceutical interventions targeting the crosslinking process and relevant clinical studies are also introduced. Limitations of pharmaceutical development may be due to the lack of systemic investigations related to the influence on crosslinking mechanism from micro to macro level, which are discussed in the last section. We also propose the unclarified questions regarding crosslinking mechanisms and potential challenges in crosslinking-targeted therapeutics development.(https://doi.org/10.1088/1748-605X/ac2b79)