The production of recombinant pharmaceutical proteins in plants is entering a new phase with the recent approval of recombinant glucocerebrosidase produced in carrot cells and the successful production of clinical-grade proteins in diverse plant-based production platforms. In the long journey from concept to product, the field of molecular farming has faced technical and economic hurdles, many reflecting the initially limited productivity of plants compared to established platforms such as mammalian cells. This challenge has been met by innovative research aiming to increase recombinant protein yields and maximize the economic benefits of plants. Research has focused on increasing the intrinsic yield capability of plants by optimizing expression construct design, and also on novel strategies to avoid epigenetic silencing and environmental effects on protein accumulation. In this article, we discuss the diverse approaches that have been used to increase the productivity of plant-based platforms for the production of recombinant pharmaceutical proteins and consider future opportunities to maximize the potential of plants and increase their competitiveness outside niche markets.