A large number of scoring functions for ranking peptide matches to observed MS/MS spectra have been discussed in the literature. In contrast to scoring functions, search strategies have received less attention, and an accurate description of search algorithms is limited. Proteomics is becoming more and more commonly used in potential clinical applications; for such approaches to be successful, the combinatorial problems from amino acid modifications and somatic and heredity SAPs (single amino acid substitutions) need to be seriously considered. The modifications and SAPs are problematic since MS and MS/MS search algorithms are optimization processes, which means that if the correct match is not iterated through during the search, then the data will be matched incorrectly, resulting in serious downstream flaws. This chapter discusses several search algorithm strategies in more detail.