A novel mathematical theory is presented allowing for a quantitative description of the various mass transport processes involved in the control of drug (in particular protein) release from lipid implants. Importantly, the model takes into account the simultaneous diffusion of multiple compounds, including the drug and water-soluble excipients, such as release modifiers (e.g., PEG) and drug stabilizers (e.g., HP-β-CD). Also dynamic changes of the implant structure resulting from drug and excipient leaching into the release medium are considered, resulting in a significant time- and position-dependent mobility of the diffusing species within the systems. Furthermore, the limited solubility of the drug and/or excipients under the given conditions in water-filled channels within the implants can be considered. This includes for instance the limited solubility of IFN-α in the presence of dissolved PEG. Importantly, good agreement between the novel theory and experimentally determined protein, PEG and HP-β-CD release kinetics from tristearin-based implants was obtained. In this particular case it could be shown that the precipitation effect of PEG on IFN-α in water-filled pores plays a crucial role for the overall control of protein release. Neglecting this phenomenon and assuming constant apparent diffusion coefficients, significant deviations between theory and experiment are observed. Importantly, the novel mathematical theory also allows for a quantitative prediction of the effects of different formulation and processing parameters on the resulting drug release kinetics. For instance the importance of the initial PEG content of the systems for the resulting IFN-α release kinetics could be successfully predicted. Interestingly, independent experiments confirmed the theoretical predictions and, thus, proved the validity and suitability of the mathematical theory.