No herbicide with a new molecular site of action (SOA) has been introduced since the 1980s. Since then, the widespread evolution of resistance of weeds to most commercial herbicides has greatly increased the need for herbicides with new SOAs. Two untried strategies for the discovery on new herbicide SOAs are discussed. Some primary metabolism intermediates are phytotoxic (e.g., protoporphyrin IX and sphingoid bases), and, because of this, the in vivo concentrations of these compounds are maintained at very low levels by plants. The determination of all primary metabolite phytotoxicities and pool sizes will identify targets of interest. Targeting SOAs that result in accumulation of phytotoxic compounds is the first novel approach to herbicide discovery. The second approach is to identify potential SOAs with very low in vivo enzyme levels. We know that higher numbers of enzyme molecules for a SOA requires more herbicide to kill a plant. Modern proteomic methods can identify low enzyme level SOAs for biorational herbicide discovery. These approaches might be useful in discovery of herbicides more closely related to natural compounds and that can be used in lower doses.