Nur77, an orphan nuclear receptor, plays a key role in T cell apoptosis. As a transcription factor, Nur77 is assumed to exert its functions by driving the expression of target genes. However, Nur77 targets in T cell apoptosis are unknown. In cancer cell lines, Nur77 can induce apoptosis through the intrinsic apoptotic pathway but it remains controversial how Nur77 kills T cells. In this study, we provide biochemical, pharmacological and genetic evidence demonstrating that Nur77 induces apoptosis through the activation of the intrinsic pathway in T cells. We also show that Nur77 is a physiological substrate of the MEK-ERK-RSK-cascade. Specifically, we demonstrate that RSK phosphorylate Nur77 at serine 354 and this modulates Nur77 nuclear export and intracellular translocation during T cell death. Our data reveal that Nur77 phosphorylation and mitochondrial targeting, regulated by RSK, may define a role for the MEK1/2-ERK1/2 cascade in T cell apoptosis.