Colorectal cancer (CRC) is a heterogeneous disease. Conventional two-dimensional (2D) culture employing cell lines was developed to study the molecular properties of CRC in vitro. Although these cell lines which are isolated from the tumor niche in which cancer develop, the translation to human model such as studying drug response is often hindered by the inability of cell lines to recapture original tumor features and the lack of heterogeneous clinical tumors represented by this 2D model, differed from in vivo condition. These limitations which may be overcome by utilizing three-dimensional (3D) culture consisting of spheroids and organoids. Over the past decade, great advancements have been made in optimizing culture method to establish spheroids and organoids of solid tumors including of CRC for multiple purposes including drug screening and establishing personalized medicine. These structures have been proven to be versatile and robust models to study CRC progression and deciphering its heterogeneity. This review will describe on advances in 3D culture technology and the application as well as the challenges of CRC-derived spheroids and organoids as a mode to screen for anticancer drugs.