Recombinant proteins (RP) are widely used as biopharmaceuticals, industrial enzymes, or sustainable food source. Yeasts, with their ability to produce complex proteins through a broad variety of cheap carbon sources, have emerged as promising eukaryotic production hosts. As such, the prevalence of yeasts as favourable production organisms in commercial RP production is expected to increase. Yet, with the selection of a robust production host on the one hand, successful scale-up is dependent on a thorough understanding of the challenging environment and limitations of large-scale bioreactors on the other hand. In the present work, several prominent yeast species, including Saccharomyces cerevisiae, Pichia pastoris, Yarrowia lipolytica, Kluyveromyces lactis and Kluyveromyces marxianus are reviewed for their current state and performance in commercial RP production. Thereafter, the impact of principal process control parameters, including dissolved oxygen, pH, substrate concentration, and temperature, on large-scale RP production are discussed. Finally, technical challenges of process scale-up are identified. To that end, process intensification strategies to enhance industrial feasibility are summarized, specifically highlighting fermentation strategies to ensure sufficient cooling capacity, overcome oxygen limitation, and increase protein quality and productivity. As such, this review aims to contribute to the pursuit of sustainable yeast-based RP production.