Squamous cell carcinoma (SCC) has a high worldwide incidence that is commonly seen as head and neck cancers, esophageal cancers, and non-small cell lung cancers. There is a poor prognosis for SCC due to potential recurrence and its metastatic tendency so the 5-year survival rate is very low. Target therapy is a novel and promising treatment strategy exhibiting great anti-tumor effects and survival benefits in SCC. This review summarizes current treatment strategies from clinical and experimental studies, including the agents targeting epidermal growth factor receptors, RNA polymerase, toll-like receptors, p38α MAPK, CXCR, and the related combination therapy regimens. However, there are still many challenges we have to face. It is a burning need to improve the development and availability of drug formulations.