Long Interspersed Nuclear Element-1 (LINE-1) are DNAs that compromise 17% of our genome. LINE-1 expression is triggered by environmental stressors and accomplished through its demethylation leading to genomic instability. Expression of LINE-1 is regulated in adult somatic tissues through several endogenous defensive mechanisms, but is found to be associated with tumorigenesis in several cancers. This finding, has inspired the use of different indicators of LINE-1 activation, as biomarkers in cancer diagnostics and even therapeutic targets in recent years. The objective of this review is to provide a critical examination of LINE-1 elements as companion cancer diagnostic/prognostic biomarkers and anti-cancer drug targets. In our view, there's great potential for LINE-1 serving at both forefronts, but there is a need for more mechanistic studies in the clinic as well as on the bench research to validate LINE-1 activation elements as cancer biomarkers or therapeutic targets; in different cancer types and/or stages of the disease. In this context, development of minimally invasive, reliable and sensitive diagnostic tools for LINE-1 activation elements for clinical use, is of priority. • Line-1 is linked to numerous cancers, and may be an elusive biomarker for diagnosis/prognosis of cancer • Activation of Line-1 can be determined through hypomethylation of the promoter, expression of mRNA, and ORF1/ORF2 protein • Non-invasive screening tools for early cancer detection show great promise to improve patient outcomes and reduce mortality • We review the promise and pitfalls of Line-1 for diagnosis, prognosis, and novel therapeutics for many human cancers [ABSTRACT FROM AUTHOR]