The growing research interest in molecular glue compounds is rapidly expanding the compilation of E3 ligases, molecular glues, their neosubstrates, and the associated diseases they treat, particularly for the degradation of previously undruggable proteins. Molecular glues have been discovered by serendipity, chemical library screening, and rationale design. Mechanism of action, structure-activity relationship, and protein-molecular glue interaction studies of initially discovered molecular glues have laid foundation for their optimization using structure-based drug design.