Methylmercury is an environmental contaminant which causes relatively specific degeneration of the granular layer of the cerebellum, despite its ability to bind thiol groups in proteins of all cell types. The mechanisms underlying the specific targeting of cells during MeHg poisoning may depend on specific receptors and other targets related to divalent cation homeostasis, particularly intracellular calcium (Ca(2+)(i) signaling. MeHg disrupts Ca(2+)(i) homeostasis in a number of neuronal models, including cerebellar granule cells in primary culture, and contributes to MeHg-induced cell death, impaired synaptic function and disruption of neuronal development. Interestingly, the disruption of [Ca(2+)](i) regulation occurs through specific pathways which affect Ca(2+) regulation by organelles, particularly mitochondria and the smooth endoplasmic reticulum (SER). Cholinergic pathways which affect [Ca(2+)](i) signaling also appear to be critical targets, particularly muscarinic acetylcholine (ACh) receptors which are linked to Ca(2+) release through inositol-1,4,5-triphosphate (IP(3)) receptors. [Ca(2+)](i) dysregulation may also underlie observed alterations in cerebellar neuron development through interaction with specific target(s) in the developing axon. In this review, we examine the hypothesis that MeHg affects specific targets to cause disruption of neuronal development and cell death.