Occupational and environmental exposure to manganese continue to represent a realistic public health problem in both developed and developing countries. Increased utility of MMT as a replacement for lead in gasoline creates a new source of environmental exposure to manganese. It is, therefore, imperative that further attention be directed at molecular neurotoxicology of manganese. A Need for a more complete understanding of manganese functions both in health and disease, and for a better defined role of manganese in iron metabolism is well substantiated. The in-depth studies in this area should provide novel information on the potential public health risk associated with manganese exposure. It will also explore novel mechanism(s) of manganese-induced neurotoxicity from the angle of Mn-Fe interaction at both systemic and cellular levels. More importantly, the result of these studies will offer clues to the etiology of IPD and its associated abnormal iron and energy metabolism. To achieve these goals, however, a number of outstanding questions remain to be resolved. First, one must understand what species of manganese in the biological matrices plays critical role in the induction of neurotoxicity, Mn(II) or Mn(III)? In our own studies with aconitase, Cpx-I, and Cpx-II, manganese was added to the buffers as the divalent salt, i.e., $MnCl_2$. While it is quite reasonable to suggest that the effect on aconitase and/or Cpx-I activites was associated with the divalent species of manganese, the experimental design does not preclude the possibility that a manganese species of higher oxidation state, such as Mn(III), is required for the induction of these effects. The ionic radius of Mn(III) is 65 ppm, which is similar to the ionic size to Fe(III) (65 ppm at the high spin state) in aconitase (Nieboer and Fletcher, 1996; Sneed et al., 1953). Thus it is plausible that the higher oxidation state of manganese optimally fits into the geometric space of aconitase, serving as the active species in this enzymatic reaction. In the current literature, most of the studies on manganese toxicity have used Mn(II) as $MnCl_2$ rather than Mn(III). The obvious advantage of Mn(II) is its good water solubility, which allows effortless preparation in either in vivo or in vitro investigation, whereas almost all of the Mn(III) salt products on the comparison between two valent manganese species nearly infeasible. Thus a more intimate collaboration with physiochemists to develop a better way to study Mn(III) species in biological matrices is pressingly needed. Second, In spite of the special affinity of manganese for mitochondria and its similar chemical properties to iron, there is a sound reason to postulate that manganese may act as an iron surrogate in certain iron-requiring enzymes. It is, therefore, imperative to design the physiochemical studies to determine whether manganese can indeed exchange with iron in proteins, and to understand how manganese interacts with tertiary structure of proteins. The studies on binding properties (such as affinity constant, dissociation parameter, etc.) of manganese and iron to key enzymes associated with iron and energy regulation would add additional information to our knowledge of Mn-Fe neurotoxicity. Third, manganese exposure, either in vivo or in vitro, promotes cellular overload of iron. It is still unclear, however, how exactly manganese interacts with cellular iron regulatory processes and what is the mechanism underlying this cellular iron overload. As discussed above, the binding of IRP-I to TfR mRNA leads to the expression of TfR, thereby increasing cellular iron uptake. The sequence encoding TfR mRNA, in particular IRE fragments, has been well-documented in literature. It is therefore possible to use molecular technique to elaborate whether manganese cytotoxicity influences the mRNA expression of iron regulatory proteins and how manganese exposure alters the binding activity of IPRs to TfR mRNA. Finally, the current manganese investigation has largely focused on the issues ranging from disposition/toxicity study to the characterization of clinical symptoms. Much less has been done regarding the risk assessment of environmenta/occupational exposure. One of the unsolved, pressing puzzles is the lack of reliable biomarker(s) for manganese-induced neurologic lesions in long-term, low-level exposure situation. Lack of such a diagnostic means renders it impossible to assess the human health risk and long-term social impact associated with potentially elevated manganese in environment. The biochemical interaction between manganese and iron, particularly the ensuing subtle changes of certain relevant proteins, provides the opportunity to identify and develop such a specific biomarker for manganese-induced neuronal damage. By learning the molecular mechanism of cytotoxicity, one will be able to find a better way for prediction and treatment of manganese-initiated neurodegenerative diseases.