Genome‐editing therapeutics are poised to treat human diseases. As we enter clinical trials with the most promising CRISPR‐Cas9 and CRISPR‐Cas12a (Cpf1) modalities, the risks associated with administering these foreign biomolecules into human patients become increasingly salient. Preclinical discovery with CRISPR‐Cas9 and CRISPR‐Cas12a systems and foundational gene therapy studies indicate that the host immune system can mount undesired responses against the administered proteins and nucleic acids, the gene‐edited cells, and the host itself. These host defenses include inflammation via activation of innate immunity, antibody induction in humoral immunity, and cell death by T‐cell‐mediated cytotoxicity. If left unchecked, these immunological reactions can curtail therapeutic benefits and potentially lead to mortality. Ways to assay and reduce the immunogenicity of Cas9 and Cas12a proteins are therefore critical for ensuring patient safety and treatment efficacy, and for bringing us closer to realizing the vision of permanent genetic cures. WIREs Syst Biol Med 2018, 10:e1408. doi: 10.1002/wsbm.1408This article is categorized under: Laboratory Methods and Technologies > Genetic/Genomic Methods Translational, Genomic, and Systems Medicine > Translational Medicine Translational, Genomic, and Systems Medicine > Therapeutic Methods