As the use of two-dimensional materials continues to grow, so too does the need to understand the environmental and biological impact of such materials. Degradation is a critical step in the life cycle of any material, but the majority of such knowledge is obtained from test tube and in vitro studies. Therefore, there remains a gap in understanding the degradability of two-dimensional materials in complex systems (in vivo) and in different ambient environments. In this Review, we highlight the need for more data-driven studies on the degradation of two-dimensional materials, including their kinetics, by-products, stability and possible downstream effects. Although challenging, building an understanding of the degradation profiles of different advanced materials in various environments at the chemical and molecular level is essential.