Extracellular production of heterologous proteins using the Escherichia coli cell factory offers several advantages over intracellular production and mammalian culture. Properly folded proteins can be rapidly accumulated in the culture media, and downstream processes for isolation and purification can be much simplified. Efforts to enhance the secretory production of target proteins can be largely classified as selection and modification of the signal peptide, co-expression of proteins to assist translocation and folding, improvement of periplasmic release, and protection of target proteins from degradation and contamination. Here, we review recent patents on the secretory production of recombinant proteins in E. coli.