MicroRNAs (miRNAs) are a class of small, non-coding RNA molecules consisting of 19-22 nucleotides that are involved in a variety of biological processes, including development, differentiation, apoptosis and cell proliferation. In cancer research, a growing body of evidence has indicated that miRNAs are aberrantly expressed in many types of human cancers and can function either as tumor suppressors or oncogenes. Bioinformatic predictions suggest that miRNAs regulate more than 30% of protein-coding genes. Aberrant expression of miRNAs in cancer cells causes destruction of miRNA-regulated messenger RNA networks. Therefore, the identification of miRNA-regulated cancer pathways is important for understanding the molecular mechanisms of human cancer. Searching for the aberrant expression of miRNAs in cancer cells is the first step in the functional analysis of miRNAs in cancer cells. Genome-wide miRNA expression signatures can rapidly and precisely reveal aberrant expression of miRNA in cancers. The miRNA expression signatures of human cancers have revealed that miR-375 is significantly downregulated in cancer cells. Our recent data on maxillary sinus, hypopharyngeal and esophageal squamous cell carcinomas have suggested that miR-375 is frequently downregulated and functions as a tumor suppressor that targets several oncogenic genes in cancer cells. In this review, we focus on several types of human squamous cell carcinoma and describe the aberrant expression of miRNAs and the cancer pathways they regulate in these diseases.