| Cancer is a genetic disease. Germline mutations in some genes cause cancer susceptibility. In sporadic cases of cancer somatic mutations in specific genes are involved in initiation and progression of cancer. Understanding the full complement of genetic changes would help better understanding of the biology of cancer. In addition, several new drugs, called targeted therapies, are becoming available that are designed to target tumors that have specific types of genetic changes. To understand the diversity of genetic and genomic changes in all major tumor types, consortia in US and around the world have initiated programs to study the genetic/genomic changes in cancer. The Cancer Genome Atlas (TCGA) and the International Cancer Genomics Consortium (ICGC) are but two examples of this effort. Among the many tumor types of the GI system, the types of changes that are observed in individual tumors include changes at the level of single nucleotides, insertions/deletions of different sizes in the genome, structural rearrangements involving tumor suppressor and oncogenes, copy number variation, changes in gene expression, changes in small and large non-coding RNAs, DNA methylation, protein modification and other changes. Among the tumors that were examined are colorectal, stomach, esophagus and pancreas. These studies have already provided important clues about the similarities of different tumor types and provided clues about possible approaches to treating different types of cancers. In the past, tumors were classified on the basis on their tissue of origin and treatments were developed on that basis. The recent genomic studies revealed that tumors from a single type of tissue can be sub classified on the basis of their genetic profile. For example, in colorectal tumors some have mutations in KRAS, BRAF, PI3 Kinase, some have copy number changes in ERBB2 and others have mutations in DNA mismatch repair genes. Each of these tumor types are being treated with specific drugs that are approved by regulatory agencies. A second feature is that the same genetic change(s) can be found in different tumor types. For example, BRAF V600 mutations are observed in melanoma, lung, colorectal and many other tumor types. These observations suggest that drugs that are approved for one tumor type may be effective in other tumor types. Genetic profiling is useful in assessing the tumor burden that can be an important biomarker for assessing the efficacy of treatment with immune check point inhibitors.