The potential marketplace for biotech-derived products from different bioprocess modifications looms large. However, there is the widespread view that, for biopharmaceuticals, the process makes the product. The current practice includes the physic-chemical and biological tests required to demonstrate structural equivalence of both products, the assessment of the potential impact of process changes on the biological quality of the products, along with their comparability in terms of safety and efficacy endpoints. Interestingly, these procedures were developed to facilitate changes in the processes applied by originators, but at present they have been extended to compare multi-source biopharmaceuticals developed by different manufacturers. Although, we must realize that, as written, the existing recommendations leave substantial room for interpretation. No universally applicable rules have been proposed, so each product must be reviewed on a case by case basis. In this context, the regulatory authorities worldwide have become increasingly aware of such a critical situation associated with this regulatory void surrounding the comparability of complex molecules. This review describes the current state of the art in comparability testing. In addition, the point that any change in process, methods, or specifications would preclude any comparability will also be addressed.