Clusterin/apolipoprotein J (CLU) gene has a nearly ubiquitous expression pattern in human tissues. The two main CLU protein isoforms in human cells include the conventional glycosylated secreted heterodimer (sCLU) and a truncated nuclear form (nCLU). CLU has been implicated in various physiological processes and in many severe physiological disturbance states including ageing, cancer progression, vascular damage, diabetes, kidney and neuron degeneration. Although unrelated in their etiology and clinical manifestation, these diseases represent states of increased oxidative stress, which in turn, promotes amorphous aggregation of target proteins, increased genomic instability and high rates of cellular death. Among the various properties attributed to CLU so far, those mostly investigated and invariably appreciated are its small heat shock proteins-like chaperone activity and its involvement in cell death regulation, which are both directly correlated to the main features of oxidant injury. Moreover, the presence of both a heat shock transcription factor-1 and an activator protein-1 element in the CLU gene promoter indicate that CLU gene can be an extremely sensitive biosensor to reactive oxygen species. This review emphasizes on CLU gene regulation by oxidative stress that is the common link between all pathological conditions where CLU has been implicated.