Fluoride has been employed in laboratory investigations since the early 20th century. These studies opened the understanding of fluoride interventions to fundamental biological processes. Millions of people living in endemic fluorosis areas suffer from various pathological disturbances. The practice of community water fluoridation used prophylactically against dental caries increased concern of adverse fluoride effects. We assessed the publications on fluoride toxicity until June 2020. We present evidence that fluoride is an enzymatic poison, inducing oxidative stress, hormonal disruptions, and neurotoxicity. Fluoride in synergy with aluminum acts as a false signal in G protein cascades of hormonal and neuronal regulations in much lower concentrations than fluoride acting alone. Our review shows the impact of fluoride on human health. We suggest focusing the research on fluoride toxicity to the underlying integrative networks. Ignorance of the pluripotent toxic effects of fluoride might contribute to unexpected epidemics in the future.