Clustered regularly interspaced short palindromic repeats (CRISPR) form the adaptive immune system in archaea and bacteria and have been modified for genome engineering in eukaryotic cells. CRISPR systems contain 2 components, a single-guide RNA, which is a short RNA composed of a 20 nucleotide sequence that targets specific sites in the genomic DNA and a scaffold necessary for its binding to the CRISPR-associated endonuclease (Cas9). Because of its high efficiency and accuracy, the CRISPR-Cas9 genome editing based therapies are poised to treat a multitude of human diseases with a promise to target previously "undruggable" proteins. As the first in-body clinical trial with CRISPR-Cas9 is embarked on, the risks associated with administering the genome editing machinery to patients become increasingly relevant. Recent studies have demonstrated an innate and adaptive cellular immune response to Cas9 in mouse models and the presence of anti-Cas9 antibodies and T-cells in human plasma. Pre-existing immunity against therapeutic Cas9 delivery could decrease its efficacy in vivo and may pose significant safety issues. This review focuses on the immunogenicity of the Cas9 protein and summarizes potential approaches to circumvent the problem of immune recognition.