Herpes simplex virus (HSV) and Epstein Barr Virus (EBV) are Herpesviridae. Although infections are often subclinical, HSV can cause mild to severe diseases, especially in immunocompromised patients. EBV infections are also often asymptomatic but this virus may be associated to carcinoma in immunocompetent patients and to severe diseases in immunocompromised patients. These viruses establish latency, in neuronal cells for HSV and in B-cells for EBV, and may reactivate, with or without symptoms. There are few drugs licensed for the treatment of HSV infections. Most of them target the viral DNA polymerase, in which acyclovir remains the reference treatment some thirty years after its discovery. The emergence of resistant viral strains, mainly in immunocompromised patients, highlights the crucial need for the development of new anti-herpes drugs that can inhibit infection by both wild-type viruses and acyclovir-resistant strains. No antiviral drug has been yet licensed for EBV. Therapies mainly rely on control of immunosuppression and/or immunotherapies. Antiviral drug such as acyclovir and ganciclovir have been used with limited impact except when used with drugs that induce EBV lytic cycle. Over the last few years, significant efforts have been made to set up a range of strategies for the identification of potential new antiviral drugs. For HSV, and more strikingly for EBV, there is a crucial need for antiviral drug active on latent virus. One alternative is to develop drugs with different mechanisms of action. The present article reviews potential targets, viral and cellular, for which specific inhibitors have been identified.