The cleavage of amyloid precursor protein (APP) by γ-secretase produces Aβ peptides, which are prominent features in Alzheimer's disease and have been extensively studied. By contrast, APP intracellular domain (AICD), also a product of this cleavage event, has received little or no investigative attention. A major reason for this is that AICD is generally not detected in tissue lysates and, therefore, is neglected as a non-relevant product of APP metabolism. However, recent studies have shown that AICD regulates a number of important cellular events. Furthermore, we found that contrary to previous assertions, AICD can be detected in brain lysates using Western blotting if an antigen retrieval protocol is employed. Here we describe the protocol for AICD detection and note the biological relevance of AICD in physiological and pathological conditions.