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.