Objectives Ezrin (Ezr), radixin (Rdx) and moesin (Msn) (ERM) proteins anchor other proteins to the cell membrane, serving to regulate their localization and function. Here, we examined whether ERM proteins functionally regulate breast cancer resistance protein (BCRP) and P‐glycoprotein in cell lines derived from lung, intestinal and renal cancers. Methods ERM proteins were each silenced with appropriate siRNA. BCRP and P‐gp functions were evaluated by means of efflux and uptake assays using 7‐ethyl‐10‐hydroxycamptothecin (SN‐38) and rhodamine123 (Rho123) as specific substrates, respectively, in non‐small cell lung cancer HCC827 cells, intestinal cancer Caco‐2 cells and renal cancer Caki‐1 cells. Key findings In HCC827 cells, the efflux rates of SN‐38 and Rho123 were significantly decreased by knockdown of Ezr or Msn, but not Rdx. However, BCRP function was unaffected by Ezr or Rdx knockdown in Caco‐2 cells, which do not express Msn. In Caki‐1 cells, Rdx knockdown increased the intracellular SN‐38 concentration, while knockdown of Ezr or Msn had no effect. Conclusions Our findings indicate that regulation of BCRP and P‐gp functions by ERM proteins is organ‐specific. Thus, if the appropriate ERM protein(s) are functionally suppressed, accumulation of BCRP or P‐gp substrates in lung, intestine or kidney cancer tissue might be specifically increased.