CRISPR-Cas9 (clustered regularly interspaced short palindromic repeats-associated protein 9) has revolutionized gene editing tools and paved the way for innovations in medical research for disease diagnosis and treatment. However, better specificity and efficient delivery of this gene machinery make it challenging to successfully edit genes for treating various diseases. This is mainly due to cellular barriers, instability in biological environments, and various off-target effects that prohibit safe and efficient delivery under in vivo conditions. This review examines several delivery modes [plasmid, mRNA, RNP (ribonucleoprotein)] and methods for the CRISPR-Cas9 system delivery, focusing on its potential applications in cancer therapy. Biocompatibility and cytotoxicity are crucial factors determining their safe and effective use. Various nanomaterials have been reviewed for their biocompatibility, limitations, and challenges in treating cancer. Among the reviewed nanoparticles, lipid nanoparticles (LNPs) stand out for their biocompatibility due to their biomimetic lipid bilayer that effectively delivers CRISPR/Cas9 cargoes while reducing toxicity. We discuss challenges in in vivo delivery and associated findings such as encapsulation, target delivery, controlled release, and endosomal escape. Future directions involve addressing limitations and adapting CRISPR-Cas9 for clinical trials, ensuring its safe and effective use.