We previously identified FERM domain containing 4A (FRMD4A) protein as a human epidermal stem cell marker that is upregulated in squamous cell carcinoma (SCC). We now show that FRMD4A is strongly expressed in SCC, regardless of differentiation status. Knockdown of FRMD4A decreases growth and metastasis of orthotopic SCC xenografts in skin and tongue. It reduces SCC proliferation and intercellular adhesion and stimulates caspase-3 activity and terminal differentiation. FRMD4A knockdown causes nuclear accumulation of YAP, indicating a role in Hippo pathway signalling. Treatment with the HSP90 inhibitor 17-DMAG or ligation of CD44 with hyaluronan, which cause nuclear depletion of FRMD4A and nuclear accumulation of YAP, reduces growth and metastasis of SCC xenografts. In addition we have developed and validated a functional antibody specific to the extracellular domain of FRMD4A. In vitro and in vivo xenograft studies with the antibody show results in concordance with the knockdown of FRMD4A at the transcriptional level. We conclude that targeting FRMD4A offers a promising new approach to treating SCC. Our results show that characterising normal tissue stem cells can provide unexpected insights into the malignant state.