In solid carbide end-mills, the flutes significantly affect the tool's cutting performance and life, and the core radius mainly affects the tool's rigidity. The current CNC programming techniques can correctly determine the orientation of the wheel so that it grinds the rake face with the specified rake angle; however, it cannot accurately determine the wheel location for the direct method and, consequently, the desired core radius is not guaranteed. To address this problem, a new CNC programming approach is proposed to accurately calculate the wheel orientation and location (WOL) in 5-axis grinding of the cylindrical end-mill flutes. In this work, a new concept of 5-axis CNC grinding—effective grinding edge (EGE)—is first proposed to represent the instantaneous grinding edge of the wheel, and the parametric equations of the effective grinding edge are formulated. The wheel orientation and location in 5-axis flute grinding are calculated automatically and accurately so that the rake angle of the rake face and the core radius are ensured. The new approach is verified with several examples in this work. Therefore, it can improve the end-mill quality and lays a good foundation for the computer-aided design/computer-aided engineering/computer-aided manufacturing (CAD/CAE/CAM) of end-mills.