The spread of tumor cells throughout the body by traveling through the bloodstream is a critical step in metastasis, which continues to be the main cause of cancer-related death. The detection and analysis of circulating tumor cells (CTCs) is important for understanding the biology of metastasis and the development of antimetastatic therapy. However, the isolation of CTCs is challenging due to their high heterogeneity and low representation in the bloodstream. Different isolation methods have been suggested, but most of them lead to CTC damage. However, viable CTCs are an effective source for developing preclinical models to perform drug screening and model the metastatic cascade. In this review, we summarize the available literature on methods for isolating viable CTCs based on different properties of cells. Particular attention is paid to the importance of in vitro and in vivo models obtained from CTCs. Finally, we emphasize the current limitations in CTC isolation and suggest potential solutions to overcome them.