Cathepsin-E is an endolysosomal aspartic proteinase and is predominantly expressed in immune system cells. Deficiency of cathepsin-E is associated with the development of atopic dermatitis, a pruritic inflammatory skin disease, which has put us to face a high selectivity challenge in the development of drugs for the therapy of Alzheimer's disease or breast cancer. This is because BACE1 (also known as beta-secretase) and cathepsin-D, both belonging to the family of aspartic proteinases, might interact with the same compound as cathepsin-E does. BACE1 is a putative prime therapeutic target for the treatment of Alzheimer's disease, and cathepsin-D a potential target for breast cancer. Accordingly, in the course of finding drugs against Alzheimer's disease or breast cancer by inhibiting BACE1 or cathepsin-D, the desired drugs should selectively inhibit only BACE1 or cathepsin-D, but definitely not cathepsin-E. To realize this, it is indispensable to find out the structural difference of the three enzymes. Since the crystal structures of BACE1 and cathepsin-D are already known, the lack of three-dimensional structure of cathepsin-E has become the bottleneck in this regard. In view of this, the three-dimensional structure of cathepsin-E has been developed. Although the overall structures of the three enzymes are quite similar to each other, some subtle difference around their active sites that distinguishes cathepsin-E from cathepsin-D and BACE1 has been revealed through an analysis of hydrogen bond network and microenvironment. The computed three-dimensional structure of cathepsin-E and the relevant findings might provide useful insights for designing inhibitors with the desired selectivity.