This chapter describes methods for comparing and aligning pairs of nucleic acid or protein sequences. The program described (SIP), the original version of which was first described in 1982 (1 ), is based around several methods for producing “dot matrix” plots and includes routines for assessing the statistical significance of the plots, plus a dynamic programming algorithm for finding optimal alignments. The end of the chapter describes a program, SIPL, that is used for comparing a single sequence against a whole library of sequences.