Small molecules are known to bind to DNA via simple intercalation, which leads to the unwinding of the DNA helix. We have demonstrated using force spectroscopy a significant reduction in the unbinding forces measured in a 16-mer DNA duplex in the presence of sequence specific and nonspecific intercalating agents, 3,6-diaminoacridine and ethidium. bromide, We also explore the effect of varying the intercalator strength on the unbinding forces measured from the DNA duplexes. At very dilute concentrations of the intercalating agents, the unbinding forces measured are similar to those measured in a hybridizing buffer.