Abstract: The invention provides a compound that inhibits the activity of 3′-tyrosyl-DNA phophodiesterase (TDP). In one embodiment, the compound is a polynucleotide-3′-bridging phosphoramidate. The invention also provides a method of inhibiting TDP activity. In one embodiment, the method involves contacting the enzyme with a polynucleotide-3′-bridging phosphoramidate, polynucleotide-3′-alkyl phosphonate, polynucleotide-3′-alkyl phosphotriester, polynucleotide-bridging-alkyl phosphonate, nucleotide-3′-bridging phosphoramidate, nucleotide-3′-alkyl phosphonate, nucleotide-3′-alkyl phosphotriester, or nucleotide-bridging-alkyl phosphonate. The invention further provides a method of decreasing cellular proliferation. The method involves contacting a TDP-containing cell with an effective amount of a TDP inhibiting compound sufficient to inhibit TDP activity in said cell. In addition, the invention provides a method of screening for compounds that modulate the activity of TDP.