In silico chemical safety assessment potentially allows for the evaluation of hazard and risk following potential exposure to a substance. A Symposium identified a number of opportunities and challenges to implement in silico methods, such as quantitative structure-activity relationships (QSARs) and read-across, to assess the potential harm of a substance in a variety of scenarios e.g. pharmaceuticals, personal care products, regulatory assessment etc. To initiate the process of in silico safety assessment, clear and unambiguous problem formulation is required to provide the context for these methods. These approaches must be built on data of defined quality, with the acknowledgement of the possibility of novel data resources tapping into on-going progress with data sharing. Models need to be developed that cover appropriate toxicity and ADME endpoints; the models being documented appropriately with defined uncertainties. The application and implementation of in silico models in chemical safety requires a flexible technological framework that enables the integration of multiple strands of data and evidence. The findings of the Symposium allowed for the identification of priorities to progress in silico chemical safety assessment to support the move towards the animal-free assessment of chemicals.