Human pluripotent stem cells play a central role in regenerative medicine and tissue engineering. These versatile cells can exist in a range of manipulable states with distinct functionalities, from the late epiblast stage represented by the conventional human embryonic stem cells (hESCs) to the mouse ESC-like naïve state. These functional states must be fully characterized if we are to harness the power of pluripotent stem cells to transform clinical medicine and therapeutics discovery.