Cancer is a genetic disease where genes regulating cell replication, growth, and differentiation become dysfunctional, largely due to mutations acquired by chance, or by the effects of the environment, heredity, or mutagens. The mutations that accumulate in a potentially malignant line of cells consist of driver genes, which push tumorigenesis forward, and passenger genes, which are the noncontributory side effects of the genomic instability that is the hallmark of neoplasia. Cancer cells therefore build up mutations within their genome, both pathogenic and nonpathogenic. The number of mutations can be measured by whole exome sequencing (WES), by targeted comprehensive genomic profiling (CGP), or by PCR. This results in an estimate of the Tumor Mutational Burden (TMB) and is expressed as the number of mutations per 1 million bases (1 megabase, or Mbase). A “normal” number of mutations in non-neoplastic tissue is about 1/Mbase. Cancers have an increased number of mutations, defined variably in the literature as low, high, and “ultrahigh.” A high TMB has been described in different studies as >10, >17, and >20 mutations/Mbase. This chapter discusses the significance of the TMB to cancer prognosis and treatment.