The combination of multi-functional machines and mobile robots supports emergence of highly flexible intelligent manufacturing systems (IMS). In this kind of manufacturing system some machines must, stay fixed at previously established positions (heavy equipment) but some types of multi-functional machines (small flexible equipment and mobile robots) can stay in one position for one or several periods and change their position for others periods, or change permanently their position in the shop floor. Moreover, using mobile robots allows performing transportation and operation Simultaneously. This possibility may change the decision processes and manufacturing system configuration, calling into question the existing decision methods in strategic, tactical mid operational levels. This paper concerns the specific production systems in which mobile robots operate in the same shop floor and at the same time with conventional and multi-functional machines and humans. This kind of production system is more sophisticated than conventional manufacturing chain (as cellular manufacturing System) and can decrease the reactivity time and new products can be quickly introduced (as for dynamic cellular manufacturing system). However, the configuration and optimization of this kind of system is very different from conventional production systems. In thiS paper, in one hand, the advantages of this kind of system and then several difficulties and challenges from operation management and industrial engineering point of view in configuration, organization, planning and optimization of IMS is discussed and developed. As a first step it is considered that localization is a key issue in the highly flexible intelligent manufacturing. Several approaches exist for outdoor localization, but indoor localization is an open problem. In this work, it is presented and discussed the highly flexible intelligent manufacturing system and the indoor localization. (C) 2015, IFAC (International Federation of Automatic Control) Hosting by Elsevier Ltd. All rights reserved.