A Mule ESB cluster consists of 2-8 Mule server instances that act as a single unit. It uses an active-active model where all servers support the application simultaneously rather than one primary server. Queues can be used to load balance across nodes. High-reliability applications require zero message loss tolerance and a reliable ESB and connections. Transports like VM and JMS are recommended for clustering over File due to distributed data access. Best practices include organizing applications into transactional steps and using reliability patterns for high reliability.