Thermal membrane distillation (TMD) is an emerging separation method which involves simultaneous heat and mass transfer through a hydrophobic semipermeable membrane. Traditionally, studies of this technology have focused on the performance of individual modules. Because of purity and recovery requirements, multiple TMD modules may be used in various configurations including series, parallel, and combinations. Furthermore, there may be a need to reroute streams from one module to another or to recycle a stream to the same unit. The objective is to develop a systematic approach to synthesize an optimal TMD network. A structural representation is developed to embed potential configurations of interest. A mathematical formulation is developed to transform the design problem into an optimization task that seeks to minimize the cost of the system. Two case studies are presented to illustrate the applicability of the developed approach and its merit over conventional design scenarios. (c) 2014 American Institute of Chemical Engineers AIChE J, 61: 448-463, 2015