Direct methanol fuel cells (DMFC) are typically a subset of polymer electrolyte membrane fuel cells (PEMFC) that possess benefits such as fuel flexibility, reduction in plant balance, and benign operation. Due to their benefits, DMFCs could play a substantial role in the future, specifically in replacing Li-ion batteries for portable and military applications. However, the critical concern with DMFCs is the degradation and inadequate reliability that affect the overall value chain and can potentially impede the commercialization of DMFCs. As a consequence, a reliability assessment can provide more insight into a DMFC component’s attributes. The membrane electrode assembly (MEA) is the integral component of the DMFC stack. A comprehensive understanding of its functional attributes and degradation mechanism plays a significant role in its commercialization. The methanol crossover through the membrane, carbon monoxide poisoning, high anode polarization by methanol oxidation, and operating parameters such as temperature, humidity, and others are significant contributions to MEA degradation. In addition, inadequate reliability of the MEA impacts the failure mechanism of DMFC, resulting in poor efficiency. Consequently, this paper provides a comprehensive assessment of several factors leading to the MEA degradation mechanism in order to develop a holistic understanding.