This chapter takes a close look at the scientific process of assessing the high comparability or similarity of a biosimilar to its corresponding innovator's biopharmaceutical from a structural perspective. In so doing, the following two areas are emphasized: the challenges that need to be overcome to successfully assess and characterize the physicochemical structure and properties of these complex drugs to obtain regulatory approval, which the FDA has already pointed out is dominated by the important issues and specific challenges concerning structural heterogeneity, HOS, and aggregation; and the analytical capabilities that are available to establish adequate physicochemical structural comparability or similarity. In considering the concepts of comparability and biosimilarity, it is helpful to note a rare situation that arose in the early 1990s that in some ways links or bridges these two concepts. The chapter also considers all types of chemical changes to a biopharmaceutical's polypeptide chain(s) inside the cell and even outside the cell as posttranslational modifications (PTMs).