Inflammatory bowel disease (IBD), consisting of ulcerative colitis (UC) and Crohn's disease (CD), is featured by overactive immune response and enduring course of unrestrained colitis. Genetic predisposition and environmental factors are fundamental in disease progression. Notably, microbiota dysregulation and its interaction with host mucosal barrier perplex disease phenotype. Under experimental setting, distinct mouse models are established to mimic human colitis process, including infection induced dysbiosis, dextran sulfate sodium (DSS) etc. induced barrier destruction, anti-CD40 L induced innate immunity dominant colitis and T cell transfer colitis model. Thus, from a more detailed aspect, IBD is heterogeneous and can be further classified into different subtypes based on the specific etiological pathways. As a typical inflammatory disorder, various immune cell types are involved in IBD pathogenesis. Among them, macrophages are believed to play a pivotal role. CX3CR1 macrophages, deriving from peripheral patrolling CD14 Ly6C monocytes, are specified cell population dwelling in the gut. Accumulating evidence suggests that CX3CR1 macrophages are critical for mucosal homeostasis and IBD pathogenesis, while some conflicts exist in current studies with both protective and harmful effects being revealed. Herein, we reviewed published literatures and found that the observed discrepancies stem from many aspects: the expression level of CX3CR1, the confounding dendritic cell subsets and most importantly, the different colitis stages and subtypes. Overall, CX3CR1 targeting strategy could be powerful weapon in fighting against colitis, but at the same time, the precise etiological and pathological mechanisms should be cautiously examined concerning the appropriate usage of CX3CR1 targeted therapy.