With the continuous improvement of the power density and operating frequency in power conversion systems, it is necessary to develop the new power electronic products with better performances than the conventional semiconductors. As a typical representative of the wide-bandgap semiconductors, gallium nitride (GaN)-based heterostructure has unique high-density two-dimensional electron gas (2DEG) and hence can be used to fabricate the fast high electron mobility transistors (HEMTs) with low power loss. Therefore, they are considered as a promising candidate for the next-generation power devices to improve the switching efficiency and speed. Compared with the depletion mode (D-mode, also known as normally-on) devices, the enhancement-mode (E-mode, also known as normally-off) devices have the advantages of safety, energy-saving, and better circuit topology design, making them more attractive for industry applications. In this paper, the different structure schemes and fabrication technologies of the GaN-based E-mode HEMTs are reviewed and summarized. Their technical characteristics are systematically compared. The influences of material epitaxial structure, ohmic contact, material etching, field plate design, and passivation process on the device performances are discussed in detail wherein the fabrication process of the recessed-gate MIS-HEMTs are emphatically illustrated, focusing on the interface treatment technology and dielectric engineering. In addition, the complicated reliability issues and physical mechanisms in the E-mode HEMTs induced by high temperature, high voltage, and high frequency switching are introduced and discussed. Finally, the potential technical solutions are proposed and the future application fields of GaN-based E-mode HEMTs are prospected.