Metallothioneins (MTs) play pivotal roles in metal-related cell homeostasis because of their high affinity for metals and their ability to form clusters. The main functional role of MTs is to sequester and/or dispense zinc, thereby participating in zinc homeostasis. Consistent with this role, MTs gene expression is transcriptionally induced by exogenous and endogenous stressing agents to protect cells from reactive oxygen species. Such protection occurs via their function as donors of zinc to antioxidant enzymes during transient stress like-conditions, such as occurs at young-adult age. Stress like-conditions are chronic during ageing, and under these conditions, MTs may sequester zinc but release too little of it because of persistent low zinc ion bioavailability. Therefore, the protective role of MTs as zinc donors may be questioned in ageing. Since zinc is required for the efficient functioning of the immune-neuroendocrine network, a lack of zinc release by MTs in ageing may switch the task of MTs from a protective one in adults to a deleterious one during ageing, with subsequent damage to immune-neuroendocrine responses. In this context, chaperone activity may be relevant because some chaperones (Hsp33, Hsp70, Hsp90), being zinc fingers, are zinc-dependent, and involved in the correct folding and intracellular trafficking of MTs, but their activity decreases with ageing. The limited zinc release by MTs in ageing might affect the chaperones activity resulting in the incorrect folding of MTs and hence leading to a further limited zinc release, which in turn affects chaperone activity itself. A vicious circle between zinc-bound MTs and chaperones might thus arise in ageing resulting in an impaired efficiency of the immune-neuroendocrine network. Zinc supplementation in ageing restores the protective role of MTs as zinc donors by correcting the balance between degradation of MTs in lysosomes, with subsequent zinc release, and the requisition of zinc by MTs themselves. A plateau in MTs levels is thus maintained and larger amounts of free zinc ions for efficient immune-neuroendocrine function are available. This restoration may also be due to correct chaperone activity, with a precise folding of MTs and reconstitution of the protective role of MTs as zinc donors. We discuss herein the role of chaperones in the trafficking and folding of MTs in immune-neuroendocrine senescence, and in relation to the possible development of a vicious circle between Zn-MTs and chaperones. The effect of zinc supply is also discussed.