Optimal management of large warehouses or regional distribution centers requires to optimally solve a number of interrelated sub-problems such as deciding the layout of the warehouse, i.e. the organization of aisles and shelves, the number of items to be made available for each stock keeping unit (SKU), the location of each SKU in the warehouse and the routing policies to be followed by pickers. These sub-problems are usually analyzed separately in the scientific literature. Moreover, real cases are often characterized by additional constraints and complicating features that are seldom considered in academic papers. We present an attempt to optimize them jointly by means of suitable mathematical optimization models and solvers. The method has been used to optimize the operations in a warehouse with an irregular layout and precedence constraints between different materials. Relevant improvements in the productivity of pickers were observed when the suggestions stemming from this analysis and optimization were compared with the company current practice.