The anthropogenic mobilization of mercury and cadmium into the biosphere has led to an increased and ineludible entry of these metals into biological systems. Here we discuss the impact of Hg(II) and Cd(II) on lipid model systems and human erythrocytes from a biophysical perspective. After a brief introduction to their implications on human health, studies that have investigated the effects of Hg(II) and Cd(II) on lipid model systems and human erythrocytes are discussed. In terms of lipids as toxicological target sites, predominantly variations in lipid head groups have been the source of investigation. However, as research in this field progresses, the effects of Hg(II) and Cd(II) on other structural features, such as acyl chain length and unsaturation, and other important lipid components and complex biomimetic lipid mixtures, will require further examinations. This review provides an analysis of what has been learned collectively from the diverse methodologies and experimental conditions used thus far. Consequently, there is a need for more comprehensive and thorough investigations into the effects of Hg(II) and Cd(II) on lipid membranes under consistent experimental conditions such as pH, ionic strength, temperature, and choice of lipid model system.