DNA mismatch repair system (DNA MMR) is a crucial genetic mechanism for DNA homeostasis in prokaryotic and eukaryotic cells. During DNA replication and also recombination, point intra-nucleotide errors including base deletion, insertion, and mis-incorporation happen. These raised abnormalities in the newly synthesized DNA strand could affect negatively the stability of the molecule and the function of the corresponding genes. DNA MMR proteins prevent these errors by recognizing and repairing them, securing directly the normal anatomy of the DNA double strand and indirectly the expression of the genes. Specific genomic alterations - mutations, loss of heterozygosity (LOH), or promoter hypermethylation - regarding the MMR genes (human homologues) hMLH1, hMSH2, hMSH3, hMSH6, hPMS1 and hPMS2 modify negatively their expression leading to loss of their function in repairing the corresponding base to base errors. The result known as microsatellite instability (MSI) was initially recognized in colonic carcinoma, especially in its inherited aspect - the Lynch syndrome -, the most common form of hereditary colon carcinoma. Since then, acquired deficiencies in specific DNA MMR genes have been detected in a broad spectrum of malignancies including different anatomic regions and histologies such as stomach, prostate, esophageal, endometrial, lung and head & neck. In the current special review we explored the role of DNA MMR deficiency in lung and oral cavity carcinomas in order to identify similarities and differences regarding the corresponding genes alterations.