The ultra-high resolution mass spectrometry such as FT-ICR-MS is the strong tool to identify the molecular compositions of natural organic matters (NOM) in aquatic water systems. The extracted NOM samples from environmental and engineered waters contain a variety of biogenic organic molecules with different origins (in both allochthonous and autochthonous origin). While molecular composition (or formula) of NOM have been well studied over the last decades, the FT-ICR-MS data for NOM samples may potentially contain an information on the fingerprint of reactions occurring in the natural and engineered systems. Studies combining with chemical and biological database (e.g., reactomics, chemoinformatics) could be emerging approach, which may provide useful information to understand transformation products and metabolites network, as well as to improve our understanding on the engineering system performance and functions of natural system. Here, we would like to discuss challenges and opportunities in the FT-ICR-MS post-analysis to further understanding the NOM functions in the natural and water treatment systems.