Microbial hydrogen production is currently hampered by lack of efficiency. We examine how hydrogen production in the hyperthermophilic bacterium Thermotoga maritima can be increased in silico. An updated genome-scale metabolic model of T. maritima was used to i) describe in detail the H-2 metabolism in this bacterium, ii) identify suitable carbon sources for enhancing H-2 production, and iii)to design knockout strains, which increased the in silico hydrogen production up to 20%. A novel synthetic oxidative module was further designed, which connects the cellular NADPH and ferredoxin pools by inserting into the model a NADPH-ferredoxin reductase. We then combined this in silica knock-in strain with a knockout strain design, resulting in an in silico production strain with a predicted 125% increase in hydrogen yield. The in silica strains designs presented here may serve as blueprints for future metabolic engineering efforts of T. maritima. Copyright (C) 2012, Hydrogen Energy Publications, LLC. Published by Elsevier Ltd. All rights reserved.