This book constitutes the proceedings of the 22nd International Conference on Comparative Genomics, RECOMB-CG 2025, which was held in Seoul, South Korea, during April 24–25, 2025. The 21 full papers presented in this book were carefully reviewed and selected from 27 submissions. The papers are divided into the following topical sections: Cancer Genomics; Homology and Reconciliation; Phylogenetics; Sequence Analysis; Epidemiology and Genome Evolution.