Genetic, transcript, and protein level variations have important functional and evolutionary consequences. We performed systematic data collection and analysis of copy-number variations, single-nucleotide polymorphisms, disease-causing variations, messenger RNA splicing variants, and protein posttranslational modifications for the genes and proteins essential for human immune system. Information about polymorphic and evolutionarily fixed genetic variations was used to group immunome genes to the most conserved and the most quickly changing ones under directed selection during the recent immunome evolution. Gene Ontology terms related to adaptive immunity are associated with gene groups subject to recent directing selection. In addition, several other characteristics of the immunome genes and proteins in these two categories have statistically significant differences. The presented findings question the usability of directed mouse genes as models for human diseases and conditions and shed light on the fine tuning of human immunity and its diverse functions. Hum Mutat 33:1456–1463, 2012. © 2012 Wiley Periodicals, Inc.