Mule clusters consist of 2-8 server instances that act as a single unit. An active-active model allows all servers to support the application simultaneously, unlike an active-passive model where only one primary server is active. To ensure reliability, applications must have zero message loss tolerance and rely on a reliable ESB and connections between clustered nodes. Best practices include organizing steps to move messages transactionally between stores, using distributed stores, and implementing reliability patterns for high reliability apps.