As one of the substitute power sources with low environmental impact and high energy density, direct methanol fuel cells (DMFCs) show great potentials in applications of portable devices, automobiles, and stationary power plants for the easy handling of liquid fuel. Challenges hindering the further commercialization of DMFCs rely on different fundamental and engineering aspects, including sluggish methanol electrochemical oxidation, methanol crossover, cathode flooding, and massive noble metal use. Herein this review, strategies addressing these issues reported in recent years are focused on the discussion of their advantages in material and structural designs, with emphasis on catalysts, membrane, electrode architecture, and flow field in multiscale consideration. By reviewing the intensively studied materials and structures for DMFC application, a holistic picture of the key component design is sketched. The future development and perspective of DMFCs in the material aspect is also discussed.