The field of cancer vaccines has moved forward dramatically, along with the progressive increase in basic knowledge of tumor immunology. During the last 20 years, a number of tumor-associated antigens have been identified, some of which have been clinically examined in patients, demonstrating encouraging results as immunotherapy against various types of cancers. However, most of the randomized clinical trials conducted to gain approval for official clinical use of the antigens have failed, due to an inability to demonstrate thair meaningful therapeutic benefit to patients over other existing treatments, with the exception of the dendritic cell(DC)-based vaccine(Provenge®), which has recently been approved as the first therapeutic cancer vaccine in the US. Such unexpected results have shed light on several important issues to solve in regard to further development of cancer vaccines. In particular, more attention should be paid to the fact that the characteristics of tumor cells and the immunological status against cancers differ widely among patients. Of note, the recent failure of cancer vaccines in clinical trials may be explained, at least in part, by the existence of a vaccine-specific adverse event; an induction of an"inconvenient immune response,"that inhibits pre-existing host immunity. Development of a novel criteria and reliable biomarkers for selecting adequate patients and vaccine antigens would be a breakthrough for further cancer vaccine development. In this review, we will summarize the current status of cancer vaccine development and discuss how to overcome negative issues raised in recently conducted clinical trials of therapeutic cancer vaccines.