Operations Research methodologies are often adopted to support the design of performance-oriented warehouse systems. The aim of this paper is to review these methodologies and contribute to a critical discussion of separate methodological results concerning i) preliminary analytical queueing solutions at a higher level, ii) detailed discrete-event simulation models at a lower level and iii) optimization procedures based on simulation in which operational policies are featured in terms of resource allocation and activity scheduling. With respect to warehouse design, today we speak of systems that are highly-supported by data in dynamic and uncertain environments. This results in a very challenging research opportunity of properly combining the above methodologies: embedding (combinatorial) optimization in a (discrete-event) simulation model to reproduce and optimize warehouse logistic processes is the main takeaway of the paper. This research avenue is not only based on the limited literature available, but also pulled by practitioners such as Italy’s largest cooperative association of general food retailers (Consorzio CONAD) whose largest member is currently the principal investigator and our partner in a research project on warehouse organization and operation.