In silico approaches are now increasingly accepted in several areas of toxicology to rapidly assess chemical hazard without the need for animal testing. Among in silico tools, quantitative and qualitative structure–activity approaches ((Q)SARs) are the most typically applied methods to predict hazard in the absence of experimental data. This paper provides an overview of different protocols that can be applied while dealing with (Q)SARs in different scenarios, namely, (Q)SAR development, use, and validation. Examples of protocols adopted in the three scenarios are reported, derived from the authors’ experience in working at the Predictive Toxicology unit of the Italian National Institute of Health, focusing on the endpoints of carcinogenicity and genotoxicity. The illustrated activities are in line with the Institute’s mission, the main center of research, control, and technical–scientific advice on public health in Italy.