A study is presented of the factors affecting the calibration of the mass scale in time-of-flight secondary ion mass spectrometry (TOF-SIMS). At the present time, TOF-SIMS analysts using local calibration procedures achieve a rather poor relative mass accuracy of only 150 ppm for large molecules (647 u) whereas for smaller fragments of <200 u this figure only improves to 60 ppm. The instrumental stability is 1 ppm and better than 10 ppm is necessary for unique identification of species. The above experimental uncertainty can lead to unnecessary confusion where peaks are wrongly identified or peaks are ambiguously assigned. Here we study, in detail, the instrumental parameters of a popular single stage reflection TOF-SIMS instrument with ion trajectory calculations using SIMION. The effect of the ion kinetic energy, emission angle, and other instrumental operating parameters on the measured peak position are determined. This shows clearly why molecular and atomic ions have different relative peak positions and the need for an aperture to restrict ions at large emission angles. These data provide the basis for a coherent procedure for optimizing the settings for accurate mass calibration and rules by which calibrations for inorganics and organics may be incorporated. This leads to a new generic set of ions for mass calibration that improves the mass accuracy in our interlaboratory study by a factor of 5. A calibration protocol is developed, which gives a relative mass accuracy of better than 10 ppm for masses up to 140 u. The effects of extrapolation beyond the calibration range are discussed and a recommended procedure is given to ensure that accurate mass is achieved within a selectable uncertainty for large molecules. Additionally, we can alternatively operate our instrument in a regime with good energy discrimination (i.e., poor energy compensation) to study the fragmented energies of molecules. This leads to data that support previous concepts developed in G-SIMS.