Manufacturing organisations are continuously forced to improve the way of working to maintain their competitiveness on the global market. To optimize a production facility requires not only an optimal design of the whole line but also its internal operations sequencing and scheduling during the operational phase. The use of Virtual Manufacturing tools such as Discrete Event Simulation and Computer Aided Robotics has been proven to be highly effective both for production system design and for operational analysis and improvement. This paper proposes a new optimisation method, named SIMBOSeer, which synergistically combines the areas of optimisation, flexibility and virtual manufacturing that integrates robot simulation with simulation-based optimisation. Evaluation of SIMBOSeer, as applied to an existing manufacturing cell at a powertrain manufacturing company in Sweden, has shown that it can be used as an iterative process of analysis and optimisation. The results, when using realistic what-if scenarios, clearly point out that SIMBOSeer can facilitate the optimisation of operation sequences and decrease the total cycle time of the manufacturing cell. This is due to the fact that many non-value adding functions, such as unnecessary tool changes, which have a great negative impact on the effectiveness of the flexible manufacturing cell, can be avoided. Whilst the use of SIMBOSeer has obvious advantages under normal operating conditions of the cell, its use become even more beneficial when disturbance like tool failures occur or when product variants are introduced to the cell.