Proteome-wide crosslinking studies have spurred great interest as they facilitate structural probing of protein interactions in living cells and organisms. However, current studies have a bias for high-abundant proteins. In a paradigm shift, we demonstrate both experimentally and by a kinetic model that this bias is caused by the propensity of crosslinks to preferentially form on high abundant proteins and not by the inability to detect crosslinks due to limitations in current technology. We further show, by using both an in-vitro mimic of a crowded cellular environment and eukaryotic cell lysates, that parameters optimized towards a pseudo 1 st order kinetics model result in a significant 3 to 10-fold overall increase in the detection of lower-abundant proteins on a proteome-wide scale. Our study therefore explains the cause of a major limitation in current proteome-wide crosslinking studies and demonstrates how to address a larger part of the proteome by crosslinking.