For patients with locoregionally recurrent head and neck squamous cell carcinoma (HNSCC), the disease is very often directly accessible for intratumoral injection. Intratumoral therapy aims to deliver the antitumor agent directly into one or more malignant lesions, with the goal of distributing the therapy as widely as possible across the disease site but also avoiding more widespread systemic dissemination of the treatment. Most therapeutic approaches aim to induce tumor death in situ, releasing tumor antigens, and locally activating components of the immune system to trigger an antitumor response (in situ vaccination) at the injected site and in locoregionally-located, draining lymph nodes. Ideally, this response will be accompanied by a more generalized systemic immune response, leading to responses at non-injected locations. Available sites for injection can include points of mucosal recurrence, especially oral and nasal cavity and parts of the pharynx that can be accessed under direct vision. The greatest number of patients with recurrent HNSCC who are considered for intratumoral therapy approaches are those with cervical lymph nodes, subcutaneous and cutaneous disease. Such sites are eminently injectable, although there may be significant safety concerns in some patients in regard to proximity of disease to the airway and neurovascular spaces in the neck. A host of directly administered agents might be considered for intratumoral therapy approaches. For the purposes of this chapter, the discussion will be restricted to three classes of agents: oncolytic viruses (specifically herpes simplex virus); genetically-modified bacteria (Yersinia enterocolitica) and a naturally-sourced, novel diterpene ester (tigilanol tiglate).