After approval of the first plant-made biopharmaceutical by FDA for human use, many protein drugs are now in clinical development. Within the last decade, significant advances have been made in expression of heterologous complex/large proteins in chloroplasts of edible plants using codon optimized human or viral genes. Furthermore, advances in quantification enable determination of in-planta drug dosage. Oral delivery of plastid-made biopharmaceuticals (PMB) is affordable because it eliminates prohibitively expensive fermentation, purification processes addressing major challenges of short shelf-life after cold storage. In this review, we discuss recent advances in PMBs against metabolic, inherited or infectious diseases, and also mechanisms of post-translational modifications (PTM) in order to increase our understanding of functional PMBs.