The acquired multidrug‐resistant metastatic head and neck squamous cell carcinoma cell line, R HSC‐3, expresses refractory cancer‐specific proteins such as the drug excretion transporter, ATP binding cassette subfamily G member 2, the cancer stem cell markers, CD44, SRY‐box transcription factor 9 and Notch, and the poor prognosis factor, fibroblast growth factor 9, and is a useful <i>in vitro</i> model for acquired multidrug resistance. The gene discussed is CD44; the disease is head and neck squamous cell carcinoma.