The main interests of my laboratory are to elucidate the mechanism of γ-secretase-dependent Notch signaling and amyloid precursor protein (APP) processing under physiological and pathological conditions and to develop target-based therapies. γ-Secretase represents a novel class of proteases that catalyze proteolysis of substrates within the transmembrane domain, an apparently hydrophobic environment, wherein water is required for peptide hydrolysis. Intramembranous proteases, including γ-secretase, site 2 proteases, rhomboids and signal peptide peptidase, play an essential role in many biological processes ranging from sterol regulation to development. Unraveling the intricacies of these enigmatic proteases is a formidable challenge that requires novel insights and approaches.