Adaptive seeds improve the efficiency and sensitivity of genomic sequence comparison. Traditional methods like BLAST use fixed-length seeds, which can be inefficient for sequences with nonuniform nucleotide composition. Adaptive seeds, instead, select matches based on their rarity, ensuring linear growth in match count and runtime with sequence length. LAST, an open-source implementation of adaptive seeds, enables fast and sensitive comparison of large, nonuniform sequences. Modern DNA data sets, such as those from whole genomes and environmental samples, are challenging to analyze due to their nonuniform composition. Comparing these sequences is essential for identifying homologous regions, predicting gene function, and mapping DNA reads. Adaptive seeds address this by reducing the number of matches and improving runtime while maintaining sensitivity. Adaptive seeds outperform fixed-length seeds in handling repetitive and nonuniform sequences. For example, in primate genomes, adaptive seeds reduce the number of matches compared to fixed-length seeds, which can generate excessive matches due to repeated elements. Similarly, in malaria genomes with high A+T content, adaptive seeds provide better sensitivity and speed. Adaptive seeds can be combined with spaced or subset seeds to further enhance performance. They are particularly effective in comparing complex genomes, such as the human and chimpanzee Y chromosomes, where repeat-rich sequences pose challenges. Adaptive seeds allow for reliable homology detection with high accuracy. Adaptive seeds also offer advantages over fixed-length seeds in other applications, such as protein sequence comparison and short read sequencing. They reduce computation time significantly, often by 10- to 100-fold, while maintaining sensitivity. LAST, the open-source software implementing adaptive seeds, has been shown to perform well compared to other alignment tools like BLAST and LASTZ. The method is efficient for genome-scale comparisons, enabling the alignment of large genomes and mapping of DNA reads. It is particularly useful for handling repetitive sequences without the need for extensive repeat-masking, which can obscure important genomic regions. Adaptive seeds provide a flexible and efficient solution for aligning large, complex biological sequences.Adaptive seeds improve the efficiency and sensitivity of genomic sequence comparison. Traditional methods like BLAST use fixed-length seeds, which can be inefficient for sequences with nonuniform nucleotide composition. Adaptive seeds, instead, select matches based on their rarity, ensuring linear growth in match count and runtime with sequence length. LAST, an open-source implementation of adaptive seeds, enables fast and sensitive comparison of large, nonuniform sequences. Modern DNA data sets, such as those from whole genomes and environmental samples, are challenging to analyze due to their nonuniform composition. Comparing these sequences is essential for identifying homologous regions, predicting gene function, and mapping DNA reads. Adaptive seeds address this by reducing the number of matches and improving runtime while maintaining sensitivity. Adaptive seeds outperform fixed-length seeds in handling repetitive and nonuniform sequences. For example, in primate genomes, adaptive seeds reduce the number of matches compared to fixed-length seeds, which can generate excessive matches due to repeated elements. Similarly, in malaria genomes with high A+T content, adaptive seeds provide better sensitivity and speed. Adaptive seeds can be combined with spaced or subset seeds to further enhance performance. They are particularly effective in comparing complex genomes, such as the human and chimpanzee Y chromosomes, where repeat-rich sequences pose challenges. Adaptive seeds allow for reliable homology detection with high accuracy. Adaptive seeds also offer advantages over fixed-length seeds in other applications, such as protein sequence comparison and short read sequencing. They reduce computation time significantly, often by 10- to 100-fold, while maintaining sensitivity. LAST, the open-source software implementing adaptive seeds, has been shown to perform well compared to other alignment tools like BLAST and LASTZ. The method is efficient for genome-scale comparisons, enabling the alignment of large genomes and mapping of DNA reads. It is particularly useful for handling repetitive sequences without the need for extensive repeat-masking, which can obscure important genomic regions. Adaptive seeds provide a flexible and efficient solution for aligning large, complex biological sequences.