With the increasing application of graphene and other two-dimensional (2D) materials, 2D materials-based devices and structures, such as flexible electronics, strain sensors, and nanocomposites, are commonly being exposed to cyclic loading and interfacial sliding/shearing and therefore have mechanical reliability concerns. Previous studies in our group have revealed high intrinsic fatigue life (> one billion cycles) of suspended pristine graphene. However, in most real applications, 2D materials contain defects and/or are mechanically loaded through interfaces/contacts which can lead to premature mechanical failure in the form of fracture and wear. In this talk recent advances in the mechanical reliability of 2D materials, such as graphene and transition metal dichalcogenides (TMDs), are presented. This includes interfacial fatigue studies of graphene/polymer, static fatigue studies of TMDs, and high cycle wear studies of graphene and TMDs.