We have used a variety of techniques to study the vesicle fusion process and elucidate the nature of the vesicle-substrate interaction and its importance in determining the mechanism of vesicle fusion. A Surface Forces Apparatus (SFA) has been used to probe the force-distance profile of a phosphotidylcholine (neutrally charged) bilayer against mica and amorphous silica surfaces in aqueous solutions. We have found that at physiological salt concentrations a significant electrostatic attraction between the dissimilar surfaces is important in determining the overall interaction. However, in the absence of salt the electrostatic force is found to be repulsive. The double-layer interaction (either attractive or repulsive), in addition to the van der Waals attraction and stabilizing fluctuation and hydration forces, combine to give the overall bilayer-silica interaction and adhesion energy. Quartz crystal microbalance (QCM) and fluorescence microscopy techniques have been employed to study the bulk vesicle fusion process and nicely complement the molecular level probing of the SFA. The results have contributed to a better understanding of the vesicle fusion mechanism and will be important in moving forward with the applications of SPBs.