Since its first observation in 1907, ortho-quinone methide (o-QM) has occupied a strategic place within the framework of reactive intermediates in organic synthesis. In recent years, o-QM has enhanced its importance as a versatile reactive intermediate, and its applications in organic synthesis, material chemistry, fine chemicals, and pharmaceuticals are increasing rapidly. This critical review summarizes the key concepts behind o-QMs and provides an overview of current applications in organic synthesis to provide an appropriate background for synthetic, medicinal and combinatorial developments. This review covers the literature from its origin to the mid of 2014 (112 references).