The genesis of any toxicological or safety outcome is multifactorial and complex; for this reason, it can be difficult for drug discovery projects to factor the avoidance of toxicity outcomes into their target design. A focus on readily measurable parameters from high-throughput in vitro assays (e.g., primary potency, clearance) is easier to handle and have become the mainstays of drug discovery projects. However, the fundamental origins of adverse safety or toxicity findings can be considered as deriving from four parameters, all of which are in the control of the drug designer. These can be described as primary pharmacology, off target pharmacology, the presence of a defined structural fragment that can be associated with adverse outcomes and the overall physicochemical properties of the molecule that may predispose it to adverse outcomes. In the drug discovery community, there has been recognition for many years of the influence of physicochemical drug properties (in particular lipophilicity) on the toxicology profile of compounds, and recent research is now beginning to quantify that risk in a probabilistic sense. This review focuses on the overall properties of classes of molecules that are associated with an increased probability of adverse outcomes in in vivo studies.