Safety assessment in early drug development relies heavily on in vitro and animal experiments. The outcome of these experiments should guide which kinds of side effects in humans can be expected. When drug development progresses in human clinical trials, progressively human safety data are becoming visible and can overrule animal data. In this context, bridging biomarkers as indicators for tissue damage in animals and that can be monitored in humans are gaining importance. There is a need for good understanding between the toxicologists and human safety specialists about the predictivity and validity of such biomarkers in terms of them being early indicators of tissue damage or just being associated with tissue damage as such or being potentially only a remote part of a pathway not important for the disease as such. Further, based on animal studies, safety concerns may emerge, for which no good surrogate markers exist. These are eg associated with aspects of covalent binging of drugs or their metabolites to proteins, processes of tumor development, genotoxicity and reproductive toxicity. In these areas of little caches of applying surrogate biomarkers or monitoring in the clinical context, it is important for the toxicologist to provide enhanced understanding of the mechanism of action in animal or in vitro studies to judge human relevance with little chances only to validate the risk assessment in the human context. In such latter cases, an enhanced effort of understanding between clinical and non-clinical safety scientists is needed. The presentation will include a few cases to illustrate this.