Ideally, a Systems Toxicology (ST) approach is aimed at by (eco)toxicologists, i.e. a multidisciplinary area incorporating classical toxicological concepts with omics technologies, and the understanding of this through computational data sciences, chemistry, mathematics, and physics modelling. As outlined in several public reports (e.g. from ECHA-European Chemical Agency and EFSA-European Food Safety Authority), the way forward in the coming years in Europe is to integrate New Approach Methodologies (NAMs) (including omics technologies) into hazard and hence risk assessment (RA). Adverse Outcome Pathways (AOPs) describe a sequence of events in response to stress, from the molecular initiating event until an adverse outcome, which is relevant to RA or regulatory decision-making. AOPs are one of the facilitators to integrate mechanistic data into RA, but it is urgent to increase the inclusion of the vast mechanistic knowledge available, especially for the RA of novel smart and advanced materials (AdMa) with multifunctional characteristics. There are still many challenges to the routine usage of NAMs, e.g. omics-based information. Here, we summarise the current state of the art of ST, the benefits of human and environmental health cross knowledge and the available methods and output. The importance of this area has been highlighted for many years but is even more pressing in the context of AdMa. Furthermore, we outline the challenges and suggest recommendations for future implementation.