PE brings convenience to people, as this plastic is cheap and performs in thousands of different forms. As PE with its high molecular weight and its stable CC bonds is recalcitrant. For decades, much work has been dedicated to screening microorganisms isolated from, e.g., soil, water, landfills, complemented with microbes from strain collections for their potential to degrade PE. However, no convincing evidence of the biodegradation of high molecular weight PE, without any pretreatment, has been presented so far. Here, we discuss potential mechanisms of PE biodegradation, especially the activation of the C-C-bond by specific or non-specific oxygenation reactions. We argue that it is doubtful that any enzyme can accept a non-water soluble, high molecular weight polymer in its highly oxidative active side. Hence, reactive oxygen species (ROS) could be a critical step toward biodegradation. Investigating the process of oxygenation may help to unravel the mystery of PE (bio)degradation. In this context, we further argue that reliable analytical methods are necessary, including stable and maybe even radioactive isotope-labelled polymers, to avoid ambiguous experimental results.