Clustered regularly interspaced short palindromic repeats and CRISPR-associated proteins (CRISPR/Cas) have revolutionized science and medicine. However, applying the CRISPR/Cas system for in vivo therapeutic genome editing remains challenging due in part to delivery obstacles. Adeno-associated virus (AAV) vectors remain one of the most promising vehicles for gene therapies, particularly in extrahepatic tissues. Nevertheless, employing AAV for in vivo CRISPR/Cas genome editing presents difficulties, including limited packaging capacity, prolonged expression, redosing complexities, modest multiplexing capability, dose-related toxicity, and immunogenicity. This thesis addresses AAV limitations in delivering CRISPR/Cas in vivo in two ways. First, I focus on developing a novel delivery modality in which the CRISPR RNA (crRNA) is delivered in the form of a naked oligonucleotide, separate from AAV-expressed effector and trans-activating crRNA (tracrRNA). I find that a short, fully stabilized oligonucleotide (a ‘protecting oligo’) can significantly enhance the potency, stability, and uptake of a heavily chemically modified crRNA. The establishment of AAV/crRNA co-delivery modality offers a route towards transient editing activity, target multiplexing, guide redosing, and vector inactivation. Second, I use a compact Nme2Cas9 adenine base editor (Nme2-ABE) to engineer a single AAV delivery system for base editing in vivo. The capability to deliver a base editor via a single AAV holds the potential to enhance safety by minimizing immune responses, mitigating dose-related toxicity, and reducing manufacturing complexity.