We describe the in vitro evaluation and crystallographic analysis of a new class of potent and selective, non-amino acid-based, small-molecule thrombin inhibitors, exemplified by 14. This class of achiral inhibitors lacks an amide-based backbone, exhibits nM inhibition of thrombin, and is selective for thrombin. Compound 14 does not interact with the active-site catalytic apparatus and is anchored to the enzyme via a single network of hydrogen bonds to Asp189 of the S1 pocket.