The effect of surface roughness on the response of the QCM has been considered, both theoretically and experimentally. A new theoretical approach to the description of the effect of roughness on the response of the QCM is proposed that accounts for the multiscale nature of roughness. Performing experiments in liquids having a wide range of viscosity and density made it possible to understand, for the first time, what characteristics of roughness influence the QCM experiments. The most important conclusion of the current study is that, to understand the experimental data, one has to take into account at least two types of roughness: slight and strong. We found that measurements of the frequency shift observed are not sufficient for the interpretations of the experimental data observed, and a full analysis of the impedance spectyum is called for.