The chemical modification of proteins is at the frontier of developments in biological imaging and biopharmaceutics. With the advent of more sensitive and higher resolution imaging techniques, researchers increasingly rely on the functionalization of proteins to enable these techniques to capture cellular processes. For biopharmaceutical therapies, chemically modified proteins, for example, antibody-drug conjugates (ADCs) offer the possibility of more tailored treatments for the disease with lower toxicities than traditional small molecule therapies. However, relatively little consideration is paid to how chemical modifications impact protein−protein interactions and solution stability. Using human γD-crystallin as a model, we demonstrate that chemical modification of the protein surface alters protein−protein interactions, which can result in lower solubility depending on the chemical nature of the modifier and the position on the protein where the modification is made. Understanding these effects is essential to ensure that modifying proteins effectively occurs with minimum self-association and that studies carried out using labeled proteins accurately reflect those of unmodified proteins.