Detrimental impacts of fluoride have become a global concern for several decades. Despite its beneficial role which is restricted only in skeletal tissues, deleterious effects are also observed in soft tissues and systems. The generation of enhanced oxidative stress is the commencement of excess fluoride exposure which may lead to cell death. Fluoride causes cell death through autophagy via Beclin 1 and mTOR signaling pathways. Beside these, several organ specific anomalies through different signaling pathways have been documented. Mitochondrial dysfunction, DNA damage, autophagy and apoptosis are the damaging outcomes in case of hepatic disorders. Urinary concentration defects and cell cycle arrest have been reported in renal tissues. Abnormal immune response has been characterized in the cardiac system. Cognitive dysfunction, neurodegenerative condition and learning impairment have also been observed. Altered steroidogenesis, gametogenic abnormalities, epigenetic alterations and birth defect are the major reprotoxic conclusions. Abnormal immune responses, altered immunogenic proliferation, differentiation as well as altered ratio of immune cells are well-defined anomalies in the immune system. Though the mechanistic approach of fluoride toxicity in physiological systems is common, it follows different signaling cascades. This review emphasizes diverse signaling pathways which are the targets of overexposed fluoride.