Abstract: The present invention relates to methods and systems for quickly determining the statistical significance of a raw alignment score produced by aligning a first sequence to a second sequence. The claimed methods and systems determine multiple estimates of the p-value of an alignment score. Each p-value estimate is then compared to a pre-defined threshold p-value. Depending upon the claimed method employed and further depending upon whether a particular p-value estimate is less than/greater than the threshold p-value, a raw alignment score may be considered statistically significant or insignificant.