Intra-tumor heterogeneity (genotypic and functional diversity among cancer cells within the same tumor) represents one of the key challenges in cancer medicine. As heterogeneity of cancer cells constitutes an important parameter in the development of therapy resistance, an accurate assessment of intra-tumor heterogeneity is essential for the prediction of drug resistance and development of effective treatment. In this review, we evaluate primary patient derived-tumor organoid technology as a new tool for colorectal cancer research and treatment. Furthermore, we discuss organoid use to understand intra-tumor heterogeneity, both in terms of mutational diversification and of diversification in drug sensitivity. Finally, we address the exciting recent results that show that tumor organoid technology is highly predictive for drug response in metastatic colorectal cancer.