Acurate control of gene-expression is essential for normal development and deregulation of transcription invariably results in human pathologies, including cancer. The dependency of tumour cells on aberrant gene-expression programs and the reliance on core-transcriptional machinery in these cells has been coined “transcriptional addiction”. Similar to cell cycle regulation, RNA Polymerase II (POLII)-driven transcription should be considered as a unidirectional multistep cycle, consisting of initiation, pausing, elongation, termination and recycling steps, which are tightly controlled by the concerted action of cyclin-dependent kinases (CDKs) and their cognate cyclins, analogous to the cyclin/CDK control of the cell cycle. I will focus on transcriptional CDKs (eg CDK7,8,9,11,12,13) and discuss how dysregulation of the transcription cycle plays an important role in cancer. I will discuss the development of small molecules targeting transcriptional CDKs as anti-cancer agents and provide a framework for the rational therapeutic application of these agents in oncology.