Plasma fractionation is the large-scale production process used to prepare an important class of protein products that are the only potential therapeutic options to treat, manage or prevent life-threatening conditions resulting from immunological disorders, congenital plasma protein deficiencies, infections and trauma. The main plasma products include immunoglobulin G (IgG), coagulation factors, fibrinogen and albumin. The core plasma fractionation process, based on sequential ethanol precipitation steps, was developed in the 1940s. It has evolved over the years through implementation of chromatographic protein purification steps, viral safety treatments and automation into a complex biotechnological process. Industrial plasma fractionation is nowadays well mastered and scientifically understood in industrialized countries; product quality and safety benefit from the mature regulations overseeing the collection of plasma and licensing of therapeutic biologicals. Several emerging countries, interested in producing plasma products from local plasma resources to increase product supplies, have considered building fractionation plants. However, the complexities of the current plasma fractionation technology and its validation constitute a substantial barrier to entry into the field. Changes in plasma product drivers in industrialized countries have raised interest in novel, easily scalable plasma fractionation technologies capable of enhancing certain aspects, such as IgG recovery. Novel plasma fractionation approaches rely (1) on multiple chromatographic steps to capture target proteins in sequence, (2) membranes and differential electric potentials to partition proteins or (3) aqueous two-phase system. A ‘mini-pool’ method of fractionation and viral inactivation using disposable devices is being developed to fill in quality gaps between crude blood components and commercial products.