Thousands of chemicals are potentially contaminating the environment and food resources, covering a wide spectrum of molecular structures, physico-chemical properties, sources, environmental behavior and toxic profiles. Beyond the description of the individual chemicals, characterizing contaminant mixtures in related matrices has become a major challenge in ecological and human health risk assessments. Continuous analytical developments, in the fields of targeted (TA) and non-targeted analysis (NTA), have resulted in ever larger sets of data on associated chemical profiles. More than ever, the implementation of advanced data analysis strategies is essential to elucidate profiles and extract new knowledge from these large data sets. Specifically focusing on the data analysis step, this review summarizes the recent progress in integrating data analysis tools into TA and NTA workflows to address the challenging characterization of chemical mixtures in environmental and food matrices. As fish matrices are relevant in both aquatic pollution and consumer exposure perspectives, fish was chosen as the main theme to illustrate this review, although the present document is equally relevant to other food and environmental matrices. The key features of TA and NTA data sets were reviewed to illustrate the challenges associated with their analysis. Advanced filtering strategies to mine NTA data sets are presented, with a particular focus on chemical filters and discriminant analysis. Further, the applications of supervised and unsupervised multivariate analysis methods to characterize exposure to chemical mixtures, and their associated challenges, is discussed.