Cytochrome P450 (P450) monooxygenases are capable of catalyzing metabolism of various endogenous and exogenous compounds, such as bile acids, fatty acids, retinoids, steroids, drugs and other xenobiotics. The enzymes, belonging to CYP1, CYP2 and CYP3 families are primarily involved in the metabolism of drugs and xenobiotics. P450-mediated defense mechanism protects organisms from the potentially toxic effects of xenobiotics to which they are exposed. The adaptive transcriptional induction of P450s by xenobiotics is mediated by aromatic hydrocarbon receptor of Per-ARNT-Sim family, and nuclear hormone receptors, including pregnane X receptor, constitutive androstane receptor and glucocorticoid receptor. In addition to the receptor-mediated induction, endogenous factors (developmental, sex or hormonal factors) can also modulate P450 expression. Steroid hormones are biologically active compounds, controlling many physiological processes via endocrine signaling pathways and contributing to the transcriptional regulation of drug metabolizing P450s. Any change in P450 activities influences the rate of activation or inactivation of drugs. Exposure to xenobiotics (drugs, environmental pollutants) can exert changes in endocrine function both directly as hormone agonists/antagonists or indirectly altering the rates of hormone metabolism and consequently the circulating levels of hormones. Modulation of P450 expression by xenobiotics can affect the subsequent metabolism of not only foreign chemicals, but also steroid hormones. Perturbation in hormone metabolism leads to the imbalance in sexual and reproductive development, and in glucose, lipid and salt/water homeostasis. The purpose of this review is to highlight the interplay between drug-metabolizing P450s and steroid hormones as well as the interactions of xenosensor with steroid signaling pathways.