The development, design, and control of the manufacturing process to obtain the biopharmaceutical of required quality, safety, and efficacy has never been more challenging, as these products have increased in size and complexity—from recombinant proteins to monoclonal antibodies to viral and non-viral vectors to genetically modified patient cells. In this chapter, the critical importance of communicating with the regulatory authorities to ensure that one’s CMC regulatory compliance strategy is appropriate and adequate will be stressed. Communicating is important, but even more important is listening to what the regulatory authority reviewers have to say, and either follow their CMC guidance or develop an alternative CMC regulatory-compliant strategy that will address the identified concerns. Taking advantage of the established regulatory review process that includes meeting opportunities throughout the clinical development program, to discuss CMC regulatory compliance strategy, reduces the risk of surprises or delays when later seeking market approval. In this chapter, the opportunities available to interact with the regulatory authority reviewers will be examined, as well as how to maximize the benefit to the biopharmaceutical manufacturer from these interactions. In this chapter, responding accurately, thoroughly, and timely to reviewers’ requests for more CMC explanation or additional data will be examined. Also, a look into the possible future changes in the CMC regulatory compliance strategy is included.