Increased competition led contractors and chemical companies to look for potential savings at every stage of the design process including the process plant layout. Decisions concerning the plant layout may affect the design, operation, production organisation, safety and construction of the plant. This work aims at developing new quantitative computer-aided methods in order to assist engineers in generating optimal process plant layouts to account for multifloor, safety and pipeless operation. A lot of research work from chemical and industrial engineers was mainly focused on single-floor process plant layout following a variety of approaches without considering the multifloor case in detail. Multifloor constructions though can reduce significantly land and operational costs and comply with current requirements for more compact plants. In this thesis efficient solution approaches are presented in order to solve the multifloor problem by determining the number of floors and the spatial allocation of equipment items to floors. A number of cost and management/engineering drivers are considered within the same framework, thus resolving various trade-offs at an optimal manner. A wide range of plants, regarding the size and the duty, have been tackled. A number of accidents in chemical plants increased the public awareness and anticpation for consideration of safety aspects during early stages of the design process. So far, they have been included in a rather simplified way in the process plant layout problem and the need for an in depth consideration is evident. Here, two different approaches are presented deciding on the allocation of items to the land area, the number and type of the protection devices installed at the items and the financial risk associated with accidents. The pipeless batch plant problem has only recently attracted the interest of the research community. Layout decisions about the allocation of processing stations in the land area are very important as they determine the vessel transfer times and affect the scheduling of both operation of processing stations and movement of vessels. In this work, a single-level approach is presented capturing layout, design and planning aspects of pipeless plants within the same framework.