Trace elements as Cu (copper), Fe (iron), and Zn (zinc) can be toxic when their distribution is not carefully regulated, and also their inappropriate binding may compromise cellular function and homeostatic mechanisms. Metal transcription factor-1 (MTF-1), a multiple Zn finger protein, activates metal response element-driven (reporter) gene expression, in a similar way as it happens in metallothionein-1 and -2 (MT-1 and MT-2), zinc transporter-1 (ZnT-1), superoxide dismutase (SOD) and γ-glutamylcysteine synthetase (γ-GCS), a rate-determining enzyme of glutathione synthesis. Virtually, MTF-1 directly coordinates the regulation of genes involved in Zn homeostasis and the protection against metal toxicity. This transcription factor is able to sense changes in metal concentrations and coordinate the expression of genes involved in acquisition, distribution, sequestration, and use of metals. This review is focused on the role of MTF-1 in regulating trace metal metabolism and gene expression of some proteins such as, for example, MT-1, MT-2 and ZnT-1. The aim of the study has been to investigate the role of MTF-1 on the Cu, Fe and Zn uptake and accumulation, and the gene expression of some proteins involved in homeostasis of trace metals in MTF-1 mutant cells as compared to their wild-type cells also were considered.