Nowadays, manufacturing companies face an increasing number of challenges that can cause unpredictable market changes. These challenges are derived from a fiercely competitive market. These challenges create unforeseen variations and uncertainties, including new regional requirements or regulations, new technologies and materials, new market segments, increasing demand for new product features, etc. To cope with the challenges above, companies must reinvent themselves and design manufacturing systems that seek to produce quality products while responding to the changes faced. These capabilities are encompassed in Reconfigurable Manufacturing Systems (RMS), capable of dealing with uncertainties quickly and economically. The availability of RMS is a crucial factor in establishing the production capacity of a system that considers all events that could interrupt the planned production. The impact of the availability in RMS is influenced by the configuration of the systems, including the number of resources used. This paper presents a case study in which a simulation-based multi-objective optimization (SMO) method is used to find machines’ optimal task allocation and assignment to workstations under different scenarios of availability. It has been shown that considering the availability of the machines affects the optimal configuration, including the number of resources needed, such as machines and buffers. This study demonstrates the importance of the availability consideration during the design of RMS.