Nuclear steroid receptors (NSR) are ligand-activated transcription factors that play a key role in a variety of vital physiological phenomena including developmental or endocrine signaling, reproduction, and homeostasis. In addition, they are implicated in other important biological processes, such as apoptosis. Modulation of apoptosis by NSR is mostly associated with control of pro-apoptotic versus anti-apoptotic gene expression, and includes both induction and prevention of apoptosis depending on cell type. However, it is unclear how NSR can affect opposing expression of the same gene in different cells. Of note, recently described nongenomic mechanisms of NSR, in particular glucocorticoid receptor translocation to mitochondria, were suggested to be crucial steps for triggering apoptosis. NSR often act solely as nuclear transporters of other regulatory molecules, thus indirectly regulating several apoptosis-related genes. Curiously, NSR are thought to cooperate with the anti-apoptotic endogenous bile acid, ursodeoxycholic acid (UDCA), to prevent programmed cell death. In fact, as cholesterol-derived molecules and due to their chemical and structural similarities to steroid hormones, bile acids also modulate NSR activation. Although the precise link between NSR and UDCA remains unclear, we have demonstrated that the bile acid requires NSR for translocation to the cell nucleus as part of a ligand-receptor complex, using a mechanism similar to that of steroid hormones. Interestingly, other studies revealed that UDCA interacts with the glucocorticoid receptor as a novel and selective NSR modifier. The huge diversity of natural ligands and xenobiotics that bind to NSR and regulate their function represents one of the most exciting drug targets for potential therapeutic intervention. The next decade will almost certainly unveil the remarkable role of NSR in modulating cell fate in human health and disease.