Among the different fuel cell technologies, the direct methanol fuel cell (DMFC) presents several interesting scientific and engineering problems such as feed and oxidant requirements, fuel utilization and recovery, scale-up, etc. There are many Process System Engineering (PSE) issues that remain unsolved. Notable among these are the structure of the DMFC and the modeling and optimization of design parameters. The PSE-related challenges discussed in this paper include the methanol and water crossover, the low kinetics rates of the reaction, heat and water management, the fuel management system, hydrodynamics studies and mass transport. Also presented in this paper are several important engineering factors for the successful stacking design of DMFCs for portable applications. Copyright (C) 2011, Hydrogen Energy Publications, LLC. Published by Elsevier Ltd. All rights reserved.