The treatment of common multi-factorial, system-wide diseases using multi-component therapeutics, such as herbal medicines, can be regarded as a “system to system” therapeutic approach. The pharmacokinetics (PK) of multi-component therapeutics is a great technical challenge, which has led to significant limitations in understanding the efficacies and toxicities of combination drugs and herbal medicines. Metabolomics has clearly demonstrated its value in elucidating the interaction of the biological systems genome with its environments, and recently been used in the PK analysis of drugs, xenobiotics and several nutrients. The metabolomics strategy can also be used in pharmacokinetic study of plant derived agents to demonstrate their biological fates, thereby linking the plant metabolome to human/ animal metabolome, and bridging the gap between multi-component agents and molecular pharmacology. This paper reviews the current progress of metabolomics based PK studies, presents the potentials and challenges of such a strategy for herbal medicines, as well as looks into the future of the role of metabolomics in the relationship between PK, PD and TOX of herbal medicines.