The need for high energy density, lightweight power sources for demanding portable applications gives incentive to the search for novel fuel cell concepts and approaches that reduce size, weight, and system complexity. Such power sources would find applications in variety of portable medical devices, computer hardware, and military equipment. This talk addresses a direct methanol fuel cell (DMFC) system approach wherein the fuel (methanol) and air are mixed and fed simultaneously to anodes and cathodes of the fuel cell stack. This overall approach leads to substantial size and weight reductions by eliminating the need for bipolar flow-field/separator plates and cell seals and by simplifying fluid manifolds. Catalyst, cell, and stack-level issues are impacted by the mixed-reactant DMFC design. The performance of promising cathode catalysts are compared to the traditional Pt catalyst, and novel hydrophilic barrier layer is applied to a PtRu anode in order to improve its performance by limiting oxygen diffusion to the anode catalyst layer. This strategy is shown to be effective despite increased ohmic resistance associated with the barrier layer.