The paper introduces a new method for aligning multiple genomic sequences, called the "threaded blockset aligner" (TBA). TBA builds a "threaded blockset," which is a generalization of the classic multiple alignment, where all matching segments occur in the same order and orientation in the given sequences. TBA is designed to align large regions of multiple mammalian genomes and can be projected onto any chosen reference genome to ensure consistent predictions of orthologous positions. The authors evaluate TBA's accuracy using simulated evolutionary changes and find that it outperforms other multiple alignment programs. TBA uses a stand-alone program called MULTIZ for dynamic-programming alignment, which can handle fragmented or rearranged sequences. The paper also describes the implementation of TBA and MULTIZ, and discusses the advantages and disadvantages of their modular versus monolithic implementation strategies. Finally, the authors highlight the need for further development to automatically generate threaded blocksets for entire mammalian genomes.The paper introduces a new method for aligning multiple genomic sequences, called the "threaded blockset aligner" (TBA). TBA builds a "threaded blockset," which is a generalization of the classic multiple alignment, where all matching segments occur in the same order and orientation in the given sequences. TBA is designed to align large regions of multiple mammalian genomes and can be projected onto any chosen reference genome to ensure consistent predictions of orthologous positions. The authors evaluate TBA's accuracy using simulated evolutionary changes and find that it outperforms other multiple alignment programs. TBA uses a stand-alone program called MULTIZ for dynamic-programming alignment, which can handle fragmented or rearranged sequences. The paper also describes the implementation of TBA and MULTIZ, and discusses the advantages and disadvantages of their modular versus monolithic implementation strategies. Finally, the authors highlight the need for further development to automatically generate threaded blocksets for entire mammalian genomes.