The tremendous success of microbial drug discovery process in the past 80 years is partly due to the parallel success of the advancement in microbial fermentation technologies.  NPI-0052 is a novel, potent proteasome inhibitor isolated from the marine actinomycete, Salinispora tropica.  It is currently undergoing clinical evaluation for the treatment of patients with various cancers.  The titer of NPI-0052 in the original fermentation conditions was 3-4 mg/L, far below the required titer for commercial development.  A fermentation development program for NPI-0052 was undertaken at Nereus Pharmaceuticals.  Nereus scientists improved the production of NPI-0052 to 450 and 360 mg/L, in shake flask and 42L lab fermentor, respectively.  Based on its potency, the 360 mg/L titer in lab fermentor is considered adequate for commercial development of NPI-0052.  The clinical supply of NPI-0052 is currently manufactured under cGMP through a robust saline fermentation process, which represents the first production of a pharmaceutical by a marine microorganism via saline fermentation.  The scheme of the fermentation development program, including media formulation, optimization of preservation method, agitation and aeration rates, selection of resin and antifoam agent, and feeding study will be presented.  In addition to improving the production of NPI-0052, the above fermentation development program also includes approaches for suppressing the production of undesirable analogs, generating new analogs, identifying new classes of secondary metabolites coproduced in the fermentation, and enhancing the robustness of the manufacturing process.