Research on the use of plants for production of protein-based therapeutics has increased tremendously since the initial experiments in the early 1990s. Plant-based expression systems offer several production advantages of low cost, rapidity, scalability, and a significantly lower chance of contamination with prion or mammalian viruses. In addition, the capability of plants in producing homogeneous N-glycans allows the development of novel therapeutics with superior efficacy and safety to their mammalian cell-produced counterparts. Various plant species have been used to develop and produce vaccines, antibodies, and pharmaceutical enzymes against a myriad of diseases by multiple expression technologies. While most of these plant-made therapeutics are in preclinical development, many have progressed into human clinical study phases and several have been approved by regulatory agencies. The current status and recent advancement of plant-based expression systems and key clinical products will be presented in this chapter. The remaining challenges and future directions for the field of plant-made therapeutics will be discussed.