There is a growing need to understand the impact of two-dimensional materials (2DMs) environmentally and on interaction with biological species, due to their increasingly wider consumer and industrial adoption. We consider degradation as a critical step in the life-cycle of any material, and the majority of such knowledge generated today is from in-test-tube and in vitro studies. We identified an existing knowledge gap on the degradability of 2DMs in complex systems (in vivo) and in different ambient environments, while more data-driven studies on degradation kinetics as a function of chemical composition could be transformative. Determination of by-products from 2DM degradation, their stability and possible downstream effects is also important. The challenges in determining a comparative degradation landscape among different advanced materials at the chemical and molecular level is considered essential.