The performance of filamentous fungi in submerged cultivation determines their suitability for large-scale industrial biotechnology processes and is the result of complex interplay between the physical and chemical parameters of the process and the cellular biology of the fungi. Filamentous fungi have a natural ability to degrade complex substrates through secretion of a large number of diverse enzymes and to produce a number of metabolites that inhibit or prevent the growth of other species in the surroundings. These features have been exploited by industry, resulting in multi-billion dollar processes for producing enzymes and metabolites of value. However, the wealth of diversity of these species is still not fully represented in large-scale bioprocesses, and thus advancement from discovery to application is one of the challenges for modern biotechnology. Acceleration of the process can be achieved through integrated approaches for assessing cellular performance (quantitative physiology), genetic modification of strains (metabolic engineering), and omics analyses and modeling (systems biology). In this review, we evaluate stateof-the-art of filamentous fungal applications in industrial biotechnology , focusing on physiological aspects of the fungi that provide the basis of their cellular performance. We also discuss the advancement of systems biology approaches and how the establishment of these tools for fungal research has begun to reveal the possibilities for further exploitation of these organisms. Increased future focus on multicellular physiology and relevant assays will lead to fungal cells and processes that are customizable to a greater degree, finally allowing the full potential of these complex organisms and their product diversity to unfold.