To achieve high availability and fault tolerance for a mission-critical application, focusing on the Reliability pillar of the AWS Well-Architected Framework is essential. This pillar ensures that a workload performs its intended function correctly and consistently when it's expected to. Designing for reliability involves setting up the application in multiple Availability Zones, ensuring decoupling of components, and employing automation to recover from failures. The other options, while important in their own right, do not directly address the high availability and fault tolerance requirements.