An alternative approach to understanding cancer and identifying therapeutic targets is to discover the key components on which the dysregulated transcriptional programs depend in cancer cells (Figure 1). Such transcriptional dependencies are not typically identified by cancer genome sequencing, but are discovered through focused mechanistic studies of gene control programs operating in both normal and neoplastic cells. We describe our current views of the transcriptional programs operating in normal cells, explain how these programs are altered in tumor cells, and discuss recent insights into components of transcriptional control on which certain cancer cells become dependent.