LINE-1 retrotransposons are ubiquitous genetic elements interspersed within the primary nuclear genome of modern day humans. Although shorter LINE-1-derived sequences occupy nearly one-in-five nucleotides of our genome, we are just beginning to appreciate the link between these important genetic elements and cancer, perhaps the most well-studied major degenerative disorder affecting humanity today. Herein, I summarize empirical observations linking LINE-1 to tumorigenesis. The work is organized into three major parts. First, I provide an overview of LINE-1 activity in cancer; highlighting major features of LINE-1 life-cycle such as: promoter methylation, transcription, translation, and retrotransposition. Second, I discuss three genetic pathways - epigenetic regulation, interferon signaling, and genome integrity – as they relate to LINE-1 regulation in cancer. Finally, I review most recent body of work linking LINE-1 as not only a diagnostic cancer biomarker, but also a potential therapeutic target.