A novel holistic approach is proposed for process retrofitting. Unlike conventional approaches, the proposed approach totally resynthesizes the entire process by incorporating the operating units with enhanced performances. As such, it can take into account all possible outcomes, including the inevitable restructuring of the flowsheet's network structure. Naturally, the proposed approach can be executed by resorting to the efficient graph-theoretic method based on P-graphs that have been originally devised for synthesizing virgin processes; nevertheless, the approach does not require the enormous effort involved in exhaustively identifying plausible operating units in synthesizing virgin processes. With the combinatorial feasibility of most operating units largely predetermined, the approach detects, with extraordinary speed, any changes in the flowsheet's network structure incurred by retrofitting. The efficacy of the approach is demonstrated by applying it to the retrofitting of a conventional downstream process for the biochemical production of butanol through the incorporation of newly identified adsorbing units.