Clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein 9 (Cas9) have fundamentally transformed the landscape of molecular biology and biomedicine. Since its adaptation as a programmable genome editing tool in 2012, CRISPR technology has expanded into a diverse ecosystem of platforms—including base editors, prime editors, and RNA-targeting systems—each offering distinct advantages in editing efficiency, target specificity, and therapeutic applicability. This review provides a comprehensive overview of contemporary CRISPR platforms, their mechanistic underpinnings, and their translation into clinical applications spanning monogenic blood disorders, ocular diseases, cardiac amyloidosis, and oncology. We further examine critical metrics—including on-target editing efficiency, off-target cleavage rates, and therapeutic outcomes—and address the ethical, regulatory, and safety considerations that accompany the clinical deployment of these transformative technologies. The approval of exagamglogene autotemcel (exa-cel) by the FDA in 2023 marks a pivotal milestone, heralding a new era of CRISPR-based medicine.