How was the development of string-matching algorithms motivated by molecular biology and biomedical science? What is an E-value for ungapped and gapped BLAST? What are the Karlin–Altschul parameters that affect E-value calculation? How do nucleotide frequencies and match-mismatch matrices affect such parameters? What are the key algorithms for FASTA and BLAST? How have these algorithms been embedded as components in other bioinformatic tools? How do their differences influence the sensitivity of sequence search? This chapter addresses these questions and illustrates applications of string matching in genomics, transcriptomics, and proteomics, as well as in drug discovery.