Freeze-drying is a fill finish operation which is commonly used to enhance the shelf life and stability of drug products. So far pharmaceutical companies paid little attention to its manufacturing cost, as it was justified by the high value of the end-to-use product. Recently, however, many drugs came off patent protection, allowing the introduction of generics into the market. As a consequence, branded companies have to face with a more competitive market, which is based on the minimum price policy. In this scenario, many pharmaceutical companies strive to enhance their production by reducing the manufacturing cost. This result is intimately connected with process intensification, which aims to optimize capital, energy and safety benefits by the development of smaller, cleaner, and energy-efficient technologies. In freeze-drying this can be achieved, e.g., through the reduction in the cycle time. In fact, freeze-drying cycles are usually longer than would be necessary. In this paper, the use of mathematical modeling for an accurate design of the process is discussed, with emphasis on the strengths and weaknesses of both in-line and off-line methods. The development of hybrid operations, where energy is transferred more efficiently through alternative sources, is also discussed. A further optimization of the process can also be obtained by the modification of the product structure, e.g., through a precise control of the nucleation temperature or using organic solvents. Finally, the paper deals with the challenge of transforming conventional batch-based systems used in pharmaceutical production into semi-continuous and finally continuous systems, as food industry did in the past five decades.