This book constitutes the refereed proceedings of the 19th Annual RECOMB Satellite Workshop on Comparative Genomics, RECOMB-CG which took place in La Jolla, USA, during May 20-21, 2022.  The 18 full papers included in this book were carefully reviewed and selected from 28 submissions. The papers were organized in topical sections on evolution; phylogenetics; homology and reconciliation; genome rearrangements; metagenomics; and genomic sequencing.