The production of megakaryocytes (MKs) – the precursors of blood platelets – from human pluripotent stem cells (hPSCs) offers exciting clinical opportunities for transfusion medicine. We describe an original approach for the large scale generation of MKs in chemically defined conditions using a forward programming strategy relying on the concurrent exogenous expression of 3 transcription factors: GATA1, FLI1 and TAL1. The forward programmed MKs proliferate and differentiate in culture for several months with MK purity over 90% reaching up to 2x105 mature MKs per input hPSC. Functional platelets are generated throughout the culture allowing the prospective collection of several transfusion units from as few as one million starting hPSCs. The high cell purity and yield achieved by MK forward programming, combined with efficient cryopreservation and GMP compatible culture, make this approach eminently suitable to both in vitro production of platelets for transfusion and basic research in MK and platelet biology.