Selection of suitable tumor-associated antigens is a major challenge in the development of effective cancer vaccines. Intratumoral (i.t.) immunotherapy empowers the immune system to mount T cell responses against tumor-associated antigens which are most immunogenic. To mediate systemic tumor regression, i.t. immunotherapy must generate systemic T cell responses that can target distant metastases beyond the initially treated tumor mass. Now that promising preclinical results and some initial success in clinical trials have been obtained, we here review i.t. immunotherapy-related preclinical and clinical studies, their mechanisms of action and future prospects.