For a little over a decade, omics methods (transcriptomics, proteomics, metabolomics, and physionomics) have been used to discover and probe the mode of action of both synthetic and natural phytotoxins. For mode of action discovery, the strategy for each of these approaches is to generate an omics profile for phytotoxins with known molecular targets and to compare this library of responses to the responses of compounds with unknown modes of action. Using more than one omics approach enhances the probability of success. Generally, compounds with the same mode of action generate similar responses with a particular omics method. Stress and detoxification responses to phytotoxins can be much clearer than effects directly related to the target site. Clues to new modes of action must be validated with in vitro enzyme effects or genetic approaches. Thus far, the only new phytotoxin target site discovered with omics approaches (metabolomics and physionomics) is that of cinmethylin and structurally related 5-benzyloxymethyl-1,2-isoxazolines. These omics approaches pointed to tyrosine amino-transferase as the target, which was verified by enzyme assays and genetic methods. In addition to being a useful tool of mode of action discovery, omics methods provide detailed information on genetic and biochemical impacts of phytotoxins. Such information can be useful in understanding the full impact of natural phytotoxins in both agricultural and natural ecosystems.