The paper describes the development and application of BLASTZ, a program for aligning human and mouse genomes. The Mouse Genome Analysis Consortium needed a sensitive alignment method to study genome evolution, particularly neutral regions. BLASTZ, an implementation of the Gapped BLAST algorithm, was modified to align entire mammalian genomes efficiently and with high sensitivity. The program was enhanced to handle lineage-specific repeats and improve alignment speed. The alignment process involved several steps, including removing repeats, extending matches, and adjusting alignments to original sequences. The results showed that BLASTZ could align a significant portion of the human and mouse genomes, with high specificity and sensitivity. The program was validated through various studies, including comparisons with reversed mouse sequences to assess specificity. The results indicated that BLASTZ could accurately align most of the human genome to the mouse genome, with high specificity. The program was also used to identify orthologous regions and to study gene duplication and synteny. The study highlights the importance of high sensitivity and specificity in aligning neutrally evolving sequences and demonstrates the effectiveness of BLASTZ in achieving these goals. The paper also discusses the computational challenges and hardware requirements for aligning large genomes, as well as the importance of validation studies in ensuring the accuracy of genomic alignments.The paper describes the development and application of BLASTZ, a program for aligning human and mouse genomes. The Mouse Genome Analysis Consortium needed a sensitive alignment method to study genome evolution, particularly neutral regions. BLASTZ, an implementation of the Gapped BLAST algorithm, was modified to align entire mammalian genomes efficiently and with high sensitivity. The program was enhanced to handle lineage-specific repeats and improve alignment speed. The alignment process involved several steps, including removing repeats, extending matches, and adjusting alignments to original sequences. The results showed that BLASTZ could align a significant portion of the human and mouse genomes, with high specificity and sensitivity. The program was validated through various studies, including comparisons with reversed mouse sequences to assess specificity. The results indicated that BLASTZ could accurately align most of the human genome to the mouse genome, with high specificity. The program was also used to identify orthologous regions and to study gene duplication and synteny. The study highlights the importance of high sensitivity and specificity in aligning neutrally evolving sequences and demonstrates the effectiveness of BLASTZ in achieving these goals. The paper also discusses the computational challenges and hardware requirements for aligning large genomes, as well as the importance of validation studies in ensuring the accuracy of genomic alignments.