With excellent physicochemical properties, inorganic nanomaterials (INMs) have exhibited a series of attractive applications in biomedical fields. Biological barriers prevent successful delivery of nanomedicine in living systems that limits the development of nanomedicine especially for sufficient delivery of drugs and effective therapy. Numerous researches have focused on overcoming these biological barriers and homogeneity of organisms to enhance therapeutic efficacy, however, most of these strategies fail to resolve these challenges. In this review, we present the latest progress about how INMs interact with biological barriers and penetrate these barriers. We also summarize that both native structure and components of biological barriers and physicochemical properties of INMs contributed to the penetration capacity. Knowledge about the relationship between INMs structure and penetration capacity will guide the design and application of functional and efficient nanomedicine in the future.