Three models describing frameshift mutations are “classical” Streisinger slippage, proposed for repetitive DNA, and “misincorporatation misalignment” and “dNTP-stabilized misalignment”, proposed for non-repetitive DNA. We distinguish between models using presteady state fluorescence kinetics to visualize transiently misaligned DNA intermediates and nucleotide incorporation products formed by DNA polymerases adept at making small frameshift mutions in vivo. Human pol catalyzes Streisinger slippage exclusively in repetitive DNA, requiring as little as a dinucleotide repeat. Escherichia coli pol IV uses dNTP-stabilized misalignment in identical repetitive DNA sequences, revealing that pol and pol IV use different mechanisms in repetitive DNA to achieve the same mutational endpoint. In non-repeat sequences, pol switches to dNTP-stabilized misalignment. Pol generates –1 frameshifts in “long” repeats and base substitutions in “short” repeats. Thus, two polymerases can use two different frameshift mechanisms on identical sequences, while one polymerase can alternate between frameshift mechanisms to process different sequences.