Cancer stem cells (CSCs) are a rare population of cancer cells exhibiting stem cell properties, such as self-renewal, differentiation and tissue restoration. Beside the initiation of the primary tumor, CSCs have also been associated with metastasis formation and cancer relapses. In the context of cancer relapses, we have recently postulated the existence of so-called recurrence CSCs (rCSCs). These specific CSC subtype will initiate relapses exhibiting an "oncogenic resistance" phenotype, which are characterized by a markedly increased malignancy concomitant with a drug resistance towards first line therapy. In the present chapter we will discuss the necessity of rCSCs as a distinct CSC subtype and that cell fusion could be one mechanism how rCSCs could originate.