Detergents are widely used for membrane protein solubilization, purification, and structural analysis. Over the past two decades, much effort has been made to design novel detergents with improved properties. Here, we provide the details of 23 different classes of novel detergents with particular focus on OGNG, LMNG, and GDN, which have been widely applied to the successful determination of a wide range of membrane protein structures. This review provides insights into the biophysical basis of the distinct behaviors of these three detergents by analysis of the stability of protein-detergent complexes (PDCs) in terms of detergent-detergent and detergent-protein interactions. The review also discusses recently developed variants of OGNG, LMNG, and GDN as well as several other classes of amphiphiles in the context of these interactions. Finally, a detailed perspective of a new detergent design is provided as a basis for expanding the applicability of small detergents for membrane protein structural study.