Organic acids are important emerging industrial building blocks. Yeasts and fungi are often natural producers of a range of organic acids, and are particularly efficient hosts because of their high tolerance to weak acids as well as to low pH, a highly desirable trait for industrial application due to reduced downstream processing costs. In concert we aim to develop two major improvements to the production of itaconic acid (IA) by fungal hosts. 1) We will optimize the production pathway, taking into account and making use of the multiple compartments in the cell. Because of these multiple compartments, we need to understand how metabolic properties of the compartments suit the production process. 2) We will address transport between compartments and eventually out of the cell. At the same time we need to improve the host organism, by reducing sensitivity to the compound and by reducing the deleterious effects that the production of IA in the cell can exert within the specific compartments in which production takes place. To do this, we take an integrative approach of genome-wide phenotypic screens to understand and reduce toxicity, metabolic modeling and engineering to understand the effects of and improve pathway topology, and detailed kinetics and novel screening for transporters to improve pathway productivity by reducing rate limiting transport steps. Such an integrated approach, focused on the Coordinatorultaneous optimization of host and pathway for the production of one specific compound, has not been previously addressed. We expect to improve the production rates of IA to levels suitable for commercialization of the fungal production process for novel bulk-scale applications that will open up new opportunities in the framework of a bio-based economy.