Chemistry, Manufacturing & Controls (CMC) regulatory compliance is essential for patient protection. But there is no “one size fits all” compliance approach for all pharmaceutical types. Compliance for biopharmaceuticals is definitely different from chemical drugs. And among the different biopharmaceutical types, there are even major compliance differences. This is not a perception, but a reality, accepted by regulatory authorities. In this chapter, four pharmaceutical types will be compared: (1) chemical drugs, (2) protein-based biopharmaceuticals [the recombinant proteins, monoclonal antibodies, and variations], (3) vector biopharmaceuticals [both viral and non-viral], and (4) genetically modified patient cells biopharmaceuticals. Across these four pharmaceutical types, four major CMC regulatory compliance areas will be examined: (1) non-living versus living source material, (2) impact of the manufacturing process on product consistency, (3) complexity of the manufactured product, and (4) biosimilars versus generics. These differences will demonstrate the complexity of the biopharmaceuticals and emphasize the need for a risk-based approach toward CMC regulatory compliance to protect patients.