Considering the risk represented by plague today as a potential biological warfare agent, we propose cytosolic Yersinia pestis dihydrofolate reductase (YpDHFR) as a new target to the design of selective plague chemotherapy. This enzyme has a low homology with the human enzyme and its crystallographic structure has been recently deposited in the Protein Data Bank (PDB). Comparisons of the docking energies and molecular dynamic behaviors of five known DHFR inhibitors inside a 3D model of YpDHFR (adapted from the crystallographic structure) and human DHFR (HssDHFR), revealed new potential interactions and suggested insights into the design of more potent HssDHFR inhibitors as well as selective inhibitors for YpDHFR.