Proton Exchange Membrane Fuel Cells (PEMFC) and Direct Methanol Fuel Cells (DMFC) have been in the forefront of all fuel cell technologies for transportation and portable power applications. This is mainly because of the quantum/semi-quantum jumps in these technologies. However, there are several techno-economic challenges for these types of fuel cells to enter the energy sector. The cell structures and operating principles of PEMFC and DMFC are similar to each other. However, techno-economic challenges for PEMFCs are significantly different from those for DMFCs, due to their applications, associated competing technologies, global market, and manufacturing environment. Both types of fuel cell are close to entering the energy sector now, more than ever before. Significant reduction of PEMFCs capital cost and miniaturization of DMFCs are two critical issues. Intense research and development efforts are needed with respect to (i) finding better and less expensive electrocatalysts and proton conducting membranes (ii) optimization of structure and composition of membrane and electrode assemblies, (iii) automation of techniques to fabricate cell and stack components, and (iv) finding efficient and cost effective methods for thermal and water management.