Classically, as a transcription factor family, the E2Fs are known to regulate the expression of various genes whose products are involved in a multitude of biological functions, many of which are deregulated in diseases including cancers. E2F is deregulated and hyperactive in most human cancers with context dependent, dichotomous and contradictory roles in almost all cancers. Cancer cells have an insatiable demand for transcription to ensure that gene products are available to sustain various biological processes that support their rapid growth and survival. In this context, cutting-off hyperactivity of transcription factors that support transcription dependence could be a valuable therapeutic strategy. However, one of the greatest challenges of targeting a transcription factor is the global effects on non-cancerous cells given that they control cellular functions in general. Recently, there is growing realization regarding the possibility to target the oncogenic activation of transcription factors to modulate transcription addiction without affecting the normal activity required for cell functions. In this review, we used E2F1 as a prototype transcription factor to address transcription factor activity in cancer cell functions. We focused on melanoma considering that E2F1 executes critical functions in response to UV, an etiological factor of cutaneous melanoma and lies immediately downstream of the CDKN2A/pRb axis, which is frequently deregulated in melanoma. Further, activation of E2F1 in melanomas can also occur independent of loss of CDKN2A. Given its activated status and the ability to transcriptionally control a plethora of genes involved in regulating melanoma development and progression, we review the current literature on its differential role in controlling signaling pathways involved in melanoma as well as therapeutic resistance, and discuss the practical value of weaning melanoma cells from E2F1-mediated transcription dependence for melanoma management.