In the open field, the environment is a critical determinant of crop yield and produce quality and it affects the geographical distribution of most crop species. In contrast, in protected cultivation, environmental control allows the fulfillment of the actual needs depending on the technological level. The economic optimum, however, depends on the trade-off between the costs of increased greenhouse control and increase in return, dictated by yield quantity, yield quality and production timing. Additional constraints are increasingly applied for achieving environmental targets. However, the diverse facets of greenhouse technology in different areas of the world will necessarily require different approaches to achieve an improved utilization of the available resources. Although advanced technologies to improve resource use efficiency can be developed as a joint effort between different players involved in greenhouse technology, some specific requirements may clearly hinder the development of common "European" resource management models that, conversely should be calibrated for different environments. For instance, the quantification and control of resource fluxes can be better accomplished in a relatively closed and fully automated system, such as those utilized in the glasshouse of Northern-Central Europe, compared to Southern Europe, where different typologies of semiopen/semi-closed greenhouse systems generally co-exist. Based on these considerations, innovations aimed at improving resource use efficiency in greenhouse agriculture should implement these aspects and should reinforce and integrate information obtained from different research areas concerning the greenhouse production. Advancing knowledge on the physiology of high temperature adaptation, for instance, may support the development and validation of models for optimizing the greenhouse system and climate management in the Mediterranean. Overall, a successful approach will see horticulturists, plant physiologists, engineers and economists working together toward the definition of a sustainable greenhouse system.