<p>Organophosphorus compounds, including pesticides and nerve agents, irreversibly inhibit acetylcholinesterase, leading to an accumulation of acetylcholine that can cause a cholinergic crisis. Standard treatment of organophosphate poisoning relies on oxime-based reactivators, such as pralidoxime, obidoxime, or asoxime. However, these compounds have several limitations, including poor penetration through the blood–brain barrier and limited efficacy across a broad spectrum of organophosphorus compounds. For this reason, non-oxime reactivators were introduced as potential alternatives. The most promising non-oxime reactivators contain Mannich phenol moiety, imidazole group or combination of both. Some of the non-oxime derivatives demonstrated better efficacy than standard oximes during in vitro evaluation. Nevertheless, these structures have significant drawbacks such as high intrinsic acetylcholinesterase inhibition or high toxicity profile which make them unsuitable for further in vivo tests. In this review, the current progress in the development of non-oxime reactivators is summarized and their bioactivity as well as their limitations are critically discussed.</p>