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Simple Summary The mechanisms underlying the effects of exogenous factors on impaired intestinal stem niche homeostasis in colorectal cancer pathogenesis are an important and ongoing focus for stem cell research. The most recent findings indicate that dysbiosis (changes in the homeostatic gut microbiota composition) can induce an aberrant reprogramming of the intestinal stem cells (ISCs) through several mechanisms, such as impaired metabolism and abnormal activation of the immune system, as well as genetic and epigenetic instability. The review goes beyond the discussion of the involvement of gut dysbiosis in colorectal cancer development, mainly summarizing the most recent findings linking the gut microbiome to colorectal cancer pathogenesis through the ISC niche impairment. The most significant advances in this field are described, focusing on different “omics” strategies, with a particular interest for the multiomics approach which will be gradually included into the framework of precision medicine. Abstract Colorectal cancer (CRC) initiation is believed to result from the conversion of normal intestinal stem cells (ISCs) into cancer stem cells (CSCs), also known as tumor-initiating cells (TICs). Hence, CRC evolves through the multiple acquisition of well-established genetic and epigenetic alterations with an adenoma-carcinoma sequence progression. Unlike other stem cells elsewhere in the body, ISCs cohabit with the intestinal microbiota, which consists of a diverse community of microorganisms, including bacteria, fungi, and viruses. The gut microbiota communicates closely with ISCs and mounting evidence suggests that there is significant crosstalk between host and microbiota at the ISC niche level. Metagenomic analyses have demonstrated that the host-microbiota mutually beneficial symbiosis existing under physiologic conditions is lost during a state of pathological microbial imbalance due to the alteration of microbiota composition (dysbiosis) and/or the genetic susceptibility of the host. The complex interaction between CRC and microbiota is at the forefront of the current CRC research, and there is growing attention on a possible role of the gut microbiome in the pathogenesis of CRC through ISC niche impairment. Here we primarily review the most recent findings on the molecular mechanism underlying the complex interplay between gut microbiota and ISCs, revealing a possible key role of microbiota in the aberrant reprogramming of CSCs in the initiation of CRC. We also discuss recent advances in OMICS approaches and single-cell analyses to explore the relationship between gut microbiota and ISC/CSC niche biology leading to a desirable implementation of the current precision medicine approaches.