In this work, a new approach to optimize facility layout for toxic release, fire and explosion scenarios is presented. By integrating a risk analysis in the optimization formulation, safer assignments for facility layout and siting have been obtained. Accompanying with the economical concepts used in a plant layout, the new model considers the cost of willing to avoid a fatality, i.e. the potential injury cost due to accidents associated with toxic release near residential areas. For fire and explosion scenarios, the building or equipment damage cost replaces the potential injury cost. Two different approaches have been proposed to optimize the total cost related with layout. In the first phase using continuous-plane approach, the overall problem was initially modeled as a disjunctive program where the coordinates of each facility and cost-related variables are the main unknowns. Then, the convex hull approach was used to reformulate the problem as a Mixed Integer Non-Linear Program (MINLP) that identifies potential layouts by minimizing overall costs. This approach gives the coordinates of each facility in a continuous plane, and estimates for the total length of pipes, the land area, and the selection of safety devices. Finally, the 3D-computational fluid dynamics (CFD) was used to compare the difference between the initial layout and the final layout in order to see how obstacles and separation distances affect the dispersion or overpressures of affected facilities. One of the CFD programs, ANSYS CFX was employed for the dispersion study and Flame Acceleration Simulator (FLACS) for the fires and explosions. In the second phase for fire and explosion scenarios, the study is focused on finding an optimal placement for hazardous facilities and other process plant buildings using the optimization theory and mapping risks on the given land in order to calculate risk in financial terms. The given land is divided in a square grid of which the sides have a certain size and in which each square acquires a risk-score. These risk-scores such as the probability of structural damage are to be multiplied by prices of potential facilities which would be built on the grid. Finally this will give us the financial risk. Accompanying the suggested safety concepts, the new model takes into account construction and operational costs. The overall cost of locations is a function of piping cost, management cost, protection device cost, and financial risk. This approach gives the coordinates of the best location of each facility in a 2-D plane, and estimates the total piping length. Once the final layout is obtained, the CFD code, FLACS is used to simulate and consider obstacle effects in 3-D space. The outcome of this study will be useful in assisting the selection of location for process plant buildings and risk management.