Herbicide tolerance in crops and weeds is considered to be monotrophic; namely determined by the relative susceptibility of the physiological process targeted, and the plant's ability to metabolise and detoxify the agrochemical. A growing body of evidence now suggests that endophytes, microbes that inhabit plant tissues and provide a range of growth, health and defence enhancements, can contribute to other types of abiotic and biotic stress tolerance. The current evidence for herbicide tolerance being bitrophic, with both free-living and plant-associated endophytes contributing to tolerance in the host plant has been reviewed. We propose that endophytes can directly contribute to herbicide detoxification through their ability to metabolise xenobiotics. In addition, the paradigm that microbes can 'prime' resistance mechanisms in plants is explored; such that they enhance herbicide tolerance by inducing the host's stress responses to withstand the downstream toxicity caused by herbicides. This latter mechanism has the potential to contribute to the growth of non-target site based herbicide resistance, in weeds. Microbial endophytes already contribute to herbicide detoxification in planta and there is now significant scope to extend these interactions using synthetic biology approaches to engineer new chemical tolerance traits into crops via microbial engineering.