In vitro release test (IVRT) using the vertical diffusion cell (VDC) is a well-established method to evaluate the performance of a topical dosage form and to better understand the physicochemical characteristics of the product. The VDC is the most frequently used apparatus to measure drug release from semisolid products and has been in use for more than fifty years; however, the technique is often hampered by high variability and inadequate reproducibility. Various method parameters influence drug release and the associated variation of the release profiles. The purpose of this manuscript is to examine the critical parameters of the VDC apparatus and the methods that are developed using it, and to highlight potential sources of variability that must be well understood to develop, validate, and implement highly effective VDC methods.