Disease biomarkers are used widely in medicine. But very few biomarkers are useful for cancer diagnosis and monitoring. Over the past 15 years, major investments have been made to discover and validate cancer biomarkers. Despite such investments, no new major cancer biomarkers have been approved for clinical use for at least 25 years. In the last decade, many reports have described new cancer biomarkers that promised to revolutionize the diagnosis of cancer and the management of cancer patients. However, many initially promising biomarkers have not been validated for clinical use. In this commentary, a plethora of parameters before sample analysis, during sample analysis, and after sample analysis that can complicate biomarker discovery and validation and lead to "false discovery" are discussed. Several examples of biomarker discoveries that were published in high-profile journals are also presented, as well as why they were not validated and the lessons learned from these false discoveries, so that similar mistakes can be avoided in the future.