This chapter provides a close look at statistical approaches by providing interpretation and/or statistical justification. It discusses some challenging issues to the Food and Drug Administration's (FDA) proposed approach. The FDA's current thinking for analytical similarity assessment using a three-tier analysis is encouraging. The chapter illustrates the stepwise approach for demonstrating biosimilarity as suggested by the FDA draft guidance. It also provides an assessment of quality attributes and brief descriptions of the equivalence test, the quality range approach, and the method of descriptive raw data and graphical comparison. Finally, the chapter provides recommendations and alternative methods for the assessment of analytical similarity in critical quality attributes (CQAs) from different tiers. For purposes of identifying CQAs at various stages of the manufacturing process, most sponsors assign CQAs based on the mechanism of action (MOA) or pharmacokinetics (PK) believed to be relevant to clinical outcomes. The three-tier approach is currently under tremendous discussion within the pharmaceutical industry and academia.