This study is devoted to the formulation of the network design problem of one-way streets and the application of simulated annealing (SA) algorithm to solve this problem for a large real network. It discusses some points of views on one-way street networks, the objective function used for design, the way in which design constraints may be considered, and the traffic problems concerning one-way streets. The results of applying the method to a real network are compared with the respective results of another heuristic approach of alternative one-way network generation, to test the goodness of SA algorithm. The SA solution to the problem became superior to any other solution at hand. Moreover, the question of the necessity of using the true values of the parameters of volume-delay functions, definition of “projects” (street segments), as well as the sufficiency of morning peak demand for design, are dealt with. Suggestions for further research end the discussion.