Polyethylene (PE) is the most abundant synthetic, petroleum-based plastic materials produced globally, and one of the most resistant to biodegradation, resulting in massive accumulation in the environment. Although the microbial degradation of polyethylene has been reported, complete biodegradation of polyethylene has not been achieved, and rapid degradation of polyethylene under ambient conditions in the environment is still not feasible. Experiments reported in the literature suffer from a number of limitations, and conclusive evidence for the complete biodegradation of polyethylene by microorganisms has been elusive. These limitations include the lack of a working definition for the biodegradation of polyethylene that can lead to testable hypotheses, a non-uniform description of experimental conditions used, and variations in the type(s) of polyethylene used, leading to a profound limitation in our understanding of the processes and mechanisms involved in the microbial degradation of polyethylene. The objective of this review is to outline the challenges in polyethylene degradation experiments and clarify the parameters required to achieve polyethylene biodegradation. This review emphasizes the necessity of developing a biochemically-based definition for the biodegradation of polyethylene (and other synthetic plastics) to simplify the comparison of results of experiments focused for the microbial degradation of polyethylene.