In this chapter, polyomaviruses will be presented in an immunological context. Principal observations will be discussed to elucidate humoral and cellular immune responses to different species of the polyomaviruses and to individual viral structural and regulatory proteins. The role of immune responses towards the viruses or their proteins in context of protection against polyomavirus induced tumors will be described. One central aspect of this presentation is the ability of polyomaviruses, and particularly large T-antigen, to terminate immunological tolerance to nucleosomes, DNA and histones. Thus, in the present chapter we will focus on clinical, experimental and theoretical aspects of the immunity to polyomaviruses.