DNA methyltransferases are promising targets for cancer therapy. In many cancer cells promoters of tumor suppressor genes are hypermethylated, which results in gene inactivation. It has been shown that DNA methyltransferase inhibitors can suppress tumor growth and have significant therapeutic value. However, the established inhibitors are limited in their application due to their substantial cytotoxicity. To discover novel compounds for the inhibition of human DNA methyltransferases, we have screened a set of small molecules available from the NCI database. Using a 3-dimensional model of the human DNA methyltransferase 1 and a modified docking and scoring procedure, we have identified a small list of molecules with high affinities for the active site of the enzyme. The two highest scoring structures were found to inhibit DNA methyltransferase activity in vitro and in vivo. The newly discovered inhibitors validate our screening procedure and also provide a useful basis for further rational drug development.