LAUSR

Precision medicine, particularly therapeutics, emphasizes the atomic‐precise, dynamic, and systems visualization of human membrane proteins and their endogenous modifiers. For years, bottom‐up proteomics has grappled with removing and avoiding detergents, yet faltered at the therapeutic‐pivotal membrane proteins, which have been tackled by classical approaches and are known for decades refractory to single‐phase aqueous or organic denaturants. Hydrophobicity and aggregation commonly challenge tissue and cell lysates, biofluids, and enriched samples. Frequently, expected membrane proteins and peptides are not identified by shotgun bottom‐up proteomics, let alone robust quantitation. This review argues the cause of this proteomic crisis is not detergents per se, but the choice of detergents. Recently, inclusion of compatible detergents for membrane protein extraction and digestion has revealed stark improvements in both quantitative and structural proteomics. This review analyzes detergent properties behind recent proteomic advances, and proposes that rational use of detergents may reconcile outstanding membrane proteomics dilemmas, enabling ultradeep coverage and minimal artifacts for robust protein and endogenous PTM measurements. The simplicity of detergent tools confers bottom‐up membrane proteomics the sophistication toward precision medicine.