A crucial parameter for activation of the anti-tumor immune response is an adequate antigen availability (AAA) defined here as the optimal tumor antigen dose and related antigen processing and MHC-II-restricted presentation necessary to efficiently trigger tumor-specific TH cells. We will discuss two distinct experimental systems: a) a preventive anti-tumor vaccination system; b) a therapy-induced anti-tumor vaccination approach. In the first case tumor cells are rendered constitutively MHC-II+ by transfecting them with the MHC-II transcriptional activator CIITA. Here AAA is generated by the function of tumor's newly expressed MHC-II molecules to present tumor-associated antigens to tumor-specific TH cells. In the second case, AAA is generated by treating established tumors with neovasculature-targeted TNFα. In conjuction with Melphalan, targeted TNFα delivery produces extensive areas of tumor necrosis that generate AAA capable of optimally activate tumor-specific TH cells which in turn activate CTL immune effectors. In both experimental systems tumor rejection and persistent and long-lived TH cell anti-tumor memory, responsible of defending the animals from subsequent challenges with tumor cells, are achieved. Based on these and other investigators' results we propose that AAA is a key element for triggering adaptive immune functions resulting in subversion from a pro-tumor to an anti-tumor microenvironment, tumor rejection and acquisition of anti-tumor immune memory. Hypotheses of neuro-immune networks involved in these approaches are discussed. These considerations are important also for the comprehension of how chemotherapy and/or radiation therapies may help to block and/or to eradicate the tumor and for the construction of suitable anti-tumor vaccine strategies.