Over the last 50 years, herbicide usage in agriculture has been extended to selective compounds applied to crops either pre- or post-emergence, as well as non-selective chemicals used in the preparation of seedbeds, for weed control around perennials and the desiccation of plant material prior to harvest. Most recently, the development of transgenic glyphosate-resistant soybean, maize, canola and cotton has massively extended the usage of normally non-selective compounds. The upshot of these major exercises in chemical selection has been the steady evolution of herbicide resistance in wild weeds, with at least 190 distinct species now affected. The mechanistic biochemistry underpinning herbicide resistance is under-studied. At a simplistic level, resistance to any chemical control agent in an organism can be brought about by: insensitivity to the disruption of activity at the target site of action (target site resistance); physical exclusion of the compound from its site of action either through lack of translocation, sequestration or active extrusion (exclusion-based resistance); or its rapid metabolism to inactive derivatives (metabolism-based resistance). The collective title of non-target site resistance associated with mechanisms 2 and 3 is generally applied where the better characterised target site resistance can be discounted. However, recent studies are now showing us that the biochemistry underlying these non-target mechanisms is both highly complex and surprisingly integrated. Non-target site resistance pathways can work together to lead to a total breakdown in chemical control. It is proposed that detoxification mechanisms underpinning metabolism-based resistance can extend to protecting the cell from the secondary damage caused by herbicide action, through mopping up reactive cellular toxins released due to membrane oxidation and derailed pathways. This general detoxification/antioxidant response has been termed co-ordinated metabolic resistance and it is proposed that this response provides the plant with a multi-tiered protection to herbicides irrespective of their mode of action. As a consequence, co-ordinated metabolic resistance can give rise to multiple herbicide resistance (MHR), which is distinct from the cross resistance observed when a change in the target site confers resistance to different herbicide chemistries which act on the same site. Co-ordinated metabolic resistance is however, only one route to generate MHR weeds. Recent studies in rigid rye-grass, Lolium rigidum, have shown that MHR can arise by aggregating multiple target site mutations and exclusion-based resistance resulting from disrupted herbicide transport. Using these resistance mechanisms as a framework, allows us to concentrate on recent developments in our understanding of the mechanisms of resistance to major classes of herbicides, highlighting instances where multiple protective mechanisms have been activated to confer MHR.