Superfamily of cytochrome P450 enzymes (CYPs), a distinctive enzyme system by which human body defends itself against toxic compounds, is the subject of a complex regulation process involving various mechanisms, on the levels of expression and activity. Apart from physiological factors, several patho-physiological ones such as inflammation, infection, and stress affect CYP expression. The aim of this review is to summarize the current knowledge on the role of microtubules network in the regulation of drug metabolizing CYPs. Experiments on human and animal cell models revealed that microtubules disruption severely impaired basal and inducible expression of human CYP 1A1, 2B6, 2C8, 2C9, 2C19, and 3A4, and rat CYP 1A2, 2B1, 2B2, and 3A23. Inhibition of aryl hydrocarbon receptor (AhR) and glucocorticoid receptor (GR) transcriptional activity by microtubules disarray was found to be responsible for the suppressed CYP enzymes expression. However, the mechanism by which microtubules interfering agents (MIAs) inhibit GR and AhR transcriptional activities is not fully understood yet. Several lines of evidence indicate that: i) the cell cycle, G2/M phase in particular, has an influence on AhR and GR transcriptional activity, and ii) MIAs negatively modulate GR transcriptional activity via the activation of c-Jun-N-terminal kinase. In conclusion, down-regulation of major CYP enzymes by microtubules disarray is intriguing from the mechanistic point of view and in relation to the cell differentiation.