Large stroke flexure mechanisms inherently lose stiffness in supporting directions when deflected. A systematic approach to synthesize such hinges is currently lacking. In this paper a new building block based spatial topology optimization method is presented for optimizing large stroke flexure hinges. This method consists of a layout variation strategy based on a building block approach combined with a shape optimization to obtain the optimal design tuned for a specific application. A derivative free shape optimization method is adapted to include multiple system boundaries and constraints to optimize high complexity flexure mechanisms in a broad solution space. To obtain the optimal layout, three predefined 3-D “building blocks” are proposed which are consecutively combined to find the best layout with respect to specific design criteria. More specifically, this new method is used to optimize a flexure hinge aimed at maximizing the frequency of the first unwanted vibration mode. The optimized topology shows an increase in frequency of a factor ten with respect to the customary three flexure cross hinge, which represents a huge improvement in performance. The numerically predicted natural frequencies and mode shapes have been verified experimentally.