Endogenous biometals, such as zinc (Zn) and copper (Cu), are essential for life and have a central role in different biochemical pathways. Genetic and environmental variables, aging, dietary intake and exposure to drugs are the most important risk factors for several human neurodegenerative disorders, including Alzheimer's disease (AD), Parkinson's Disease (PD), Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS). All induce metal ion dyshomeostasis, that in turn may have a relevant role in disease development and progression. Interestingly, Clioquinol (CQ) – a Cu and Zn ionophore that is able to cross the blood–brain barrier (BBB) – has been tested and has shown efficacy in a phase II clinical trial, slowing the rate of cognitive decline in AD and in other neurodegenerative disease models. PBT2, a second generation 8-OH quinoline derivate of CQ, has also been shown to promote neuroprotection and delay the cognitive impairment in AD transgenic models. On the other hand, defects in neurotrophin (NTF) signaling, transport or processing are causally linked to human neurodegenerative disorders, suggesting that a reciprocal interplay between the balance of metal ions and trophic factor (TF)-dependent signaling could further contribute to neuronal loss in vivo. Future pharmacological strategies that are aimed at restoring metal homeostasis and NTF intracellular pathways are currently assumed to have clinically potential, showing increasing promise as disease-modifying agents for several devastating neurological conditions.