Since early stages of bioinformatics, substrings played a crucial role in the search and discovery of significant biological signals. Despite the advent of a large number of different approaches and models toaccomplish these tasks, substrings continue to be widely used to determine statistical distributions and compositions of biological sequences at various levels of details. Here we overview efficient algorithms that were recently proposed to compute the actual and the expected frequency for words with k mismatches, when it is assumed that the words of interest occur at least once exactly in the sequence under analysis. Efficiency means these algorithms are polynomial in k rather than exponential as with an enumerative approach, and independent on the length of the query word. These algorithms are all based on a common incremental approach of a preprocessing step that allows to answer queries related to any word occurring in the text efficiently. The same approach can be used with a sliding window scanning of the sequence to compute the same statistics for words of fixed lengths, even more efficiently. The efficient computation of both expected and actual frequency of sub- strings, combined with a study on the monotonicity of popular scores such as z-scores, allows to build tables of feasible size in reasonable time, and can therefore be used in practical applications.