The article introduces SOAP (Short Oligonucleotide Alignment Program), a tool designed for efficient alignment of short oligonucleotides onto reference sequences, particularly suitable for large-scale resequencing using high-throughput sequencing technologies like Illumina-Solexa. SOAP supports both gapped and ungapped alignments and is compatible with various applications, including single-read or pair-end resequencing, small RNA discovery, and mRNA tag sequence mapping. The program is command-driven, supports multi-threaded parallel computing, and includes a batch module for multiple query sets. It allows for a certain number of mismatches or one continuous gap in the alignment and can handle iterative trimming of 3′-end errors. SOAP uses a seed and hash look-up table algorithm to accelerate alignment, converting reads and reference sequences to numeric data types. It has been shown to be significantly faster and more sensitive than traditional alignment tools like blastn, especially for gapped alignments, which are crucial for identifying small indels. The article also provides a detailed comparison of SOAP's performance and sensitivity with other alignment programs on a real dataset.The article introduces SOAP (Short Oligonucleotide Alignment Program), a tool designed for efficient alignment of short oligonucleotides onto reference sequences, particularly suitable for large-scale resequencing using high-throughput sequencing technologies like Illumina-Solexa. SOAP supports both gapped and ungapped alignments and is compatible with various applications, including single-read or pair-end resequencing, small RNA discovery, and mRNA tag sequence mapping. The program is command-driven, supports multi-threaded parallel computing, and includes a batch module for multiple query sets. It allows for a certain number of mismatches or one continuous gap in the alignment and can handle iterative trimming of 3′-end errors. SOAP uses a seed and hash look-up table algorithm to accelerate alignment, converting reads and reference sequences to numeric data types. It has been shown to be significantly faster and more sensitive than traditional alignment tools like blastn, especially for gapped alignments, which are crucial for identifying small indels. The article also provides a detailed comparison of SOAP's performance and sensitivity with other alignment programs on a real dataset.