Recombinant pharmaceutical proteins account for a significant portion of the multi-billion-dollar pharmaceutical industry. Among various potential cell factories, yeast has attracted great attention in pharmaceutical protein synthesis due to its unicellular and eukaryotic properties, easy genetic manipulation, fast growth, as well as capability of post-translational modifications. In this review, recent advances in glycoengineering of yeast and secretory mechanisms in yeast for the production of biopharmaceutical proteins with appropriate pharmacokinetic properties are overviewed. To further improve these two aspects of yeast engineering, strain and pathway engineering studies are necessary to unveil engineered yeast cell factories providing humanized glycosylation with appropriate homogeneity and high secretory therapeutic production with high yield. In addition, current systems and synthetic biology tools and omics technologies to enhance the production of pharmaceutical proteins are briefly discussed. Integration of comprehensive systems biology models with omics technologies will open new doors to better understanding of yeast glycosylation and secretory mechanism, which will help obtain valuable information for strain and pathway engineering approaches. On the other hand, the applications of currently available synthetic biology tools such as CRISPR/Cas9 and TALENs in yeast engineering will further help researchers manipulate yeast strains for high secretory recombinant therapeutic protein production with desired features. All in all, currently available systems and synthetic biology tools can be applied to yeast engineering for improved biopharmaceutical protein production.