Some elements are essential for life and others closely related to them are very toxic. In exploiting unique ecological niches many prokaryotes have evolved the means to defend themselves against and even to derive energy from deleterious elements. Toxic metal defense systems are related to those providing homeostasis of essential metals and metalloid elements. Expression of these multiprotein systems is costly but they must respond rapidly and, so, all are well controlled. Seven diverse families of metalloregulators are presently recognized for essential metal homeostasis in prokaryotes. Two of these, the ArsR and MerR families, figure more often than the others in controlling responses to toxic transition metals and metalloids. This review emphasizes recent advances in these two metalloregulator families and highlights emerging regulatory motifs of other types.