The branch of cancer immunotherapeutics leading to the vaccine effort arguably began with Coley's use of bacterial toxins to induce immune activation around the turn of the twentieth century. Through the experience gained in dozens of cancer vaccine trials and a multitude of preceding preclinical studies, a number of approaches have been defined, along with the associated major development problems and challenges. The lack of a licensed  cancer vaccine underscores the difficulty of the approach, ascribable to a number of complex and interrelated factors. Chief among the factors is the underlying global immune dysregulation in patients with advanced cancer, in particular the tumor microenvironment. Malignant tumors adapt in multiple ways to avoid immune attack, including downregulation of tumor antigens on the cell surface, production of inhibitory cytokines, and induction of anergy in infiltrating lymphocytes – all of which overwhelm any attempts to stimulate innate and adaptive immunity.