In 1996, Caplen came to the National Human Genome Research Institute at NIH as a visiting fellow, where she initially conducted studies investigating hybrid viral vectorsystems. It was while at NHGRI that Caplen developed a research interest in the newly identified gene silencing mechanism, RNA interference leading to her studies that establish the presence of RNAi in mammalian cells. Caplen joined the Center for Cancer Research at the National Cancer Institute in 2004 as a Senior Scientist, where she pioneered approaches for exploiting RNAi to investigate cancer biology and treatment and helped establish a trans-NIH facility for genome-wide RNAi screening. Caplen was appointed a tenure-track investigator in CCR's Genetics Branch in January 2016. She is head of the functional genetics section. Her research focuses on using functional genetic methods to interrogate specific aspects of the genetic, transcriptional, and signaling alterations observed in cancers driven by fusion oncogenes.