Several efforts have been made in developing strategies to supply the enzyme market, as well as in reducing its costs. It includes the selection of an appropriate enzyme source and the optimization of enzyme properties and secretion. Carbohydrate-Active Enzymes (CAZymes) are industrially relevant biocatalysts that are capable of degrading plant cell wall biomass. The most important secreted enzymes related to plant cell wall decomposition are cellulases, hemicellulases, and auxiliary enzymes. These enzymes have been applied in the hydrolysis of plant biomass for the production of second-generation (2G) ethanol and several other high added value products. One of the bottlenecks for 2G ethanol production is the cost of enzymes applied on plant biomass hydrolysis. The improvement of proteins production by fungi applying system biology and genetic engineering is an interesting and promising strategy to reduce the enzymes cost and make the 2G ethanol production viable. Fungi play an important role in plant biomass degradation and biotechnology by producing and secreting high yields of enzymes. In spite of the fact that filamentous fungi present several advantages compared to other microorganisms due to the high level of proteins production, heterologous protein production is far from optimal levels and still needs to be improved. Currently, heterologous production of certain proteins is generally considerably lower than the levels obtained to homologous production. Many strategies have been studied in order to improve heterologous production of proteins by filamentous fungi, including the deletion of genes that encode for proteases, the deletion of lectin-like ER-Golgi cargo receptors and the co-expression of specific chaperones. It has been shown that the main bottleneck in the production of heterologous proteins is not caused by the low expression of the target gene. An experimental evidence suggests that most target proteins produced in filamentous fungi are lost or stuck in the secretory pathway due to errors in processing, modification or misfolding that result in their elimination by endoplasmic reticulum (ER) quality control. Misfolded proteins alter homeostasis and proper ER functioning resulting in a state known as ER stress. ER stress activates a conserved signaling pathway called unfolded protein response (UPR) and ER-associated protein degradation (ERAD), which upregulates genes responsible for restoring protein folding homeostasis in the cell and degrades misfolded protein in the cytosol by the ubiquitin-proteasome system. The genetic manipulation of individual genes and changes in the genome seems not to be the best alternative to overcome the main bottlenecks in heterologous protein secretion. However, the understanding of complex interactions of important proteins and genes, as well as how they are regulated is more promising.