Monocytes play a critical role in atherosclerosis, with two major subsets—CCR2⁺Ly-6C⁺ and CCR2⁻Ly-6C⁻—differing in their chemokine receptor usage. CCR2 and CX3CR1 are linked to atherosclerotic plaque progression. In apoE-deficient mice, CCR2⁺Ly-6C⁺ monocytes efficiently accumulate in plaques, while CCR2⁻Ly-6C⁻ monocytes enter less frequently but are more likely to differentiate into CD11c⁺ cells, indicating distinct roles in plaque heterogeneity. CCR2⁻ monocytes rely on CCR5 for entry, whereas CCR2⁺ monocytes require both CCR2 and CX3CR1. This suggests that CX3CR1 is crucial for CCR2⁺ monocyte recruitment to plaques, unlike in other inflammatory settings where CCR2 is sufficient. Targeting CX3CR1 may be effective in reducing atherosclerosis without impairing CCR2-dependent inflammatory responses. The study used latex bead labeling to trace monocyte subsets and their differentiation in plaques, revealing that CCR2⁺ monocytes use CCR2 and CX3CR1, while CCR2⁻ monocytes rely on CCR5. These findings highlight the distinct roles of chemokine receptors in monocyte recruitment and plaque development, with implications for therapeutic strategies targeting atherosclerosis.Monocytes play a critical role in atherosclerosis, with two major subsets—CCR2⁺Ly-6C⁺ and CCR2⁻Ly-6C⁻—differing in their chemokine receptor usage. CCR2 and CX3CR1 are linked to atherosclerotic plaque progression. In apoE-deficient mice, CCR2⁺Ly-6C⁺ monocytes efficiently accumulate in plaques, while CCR2⁻Ly-6C⁻ monocytes enter less frequently but are more likely to differentiate into CD11c⁺ cells, indicating distinct roles in plaque heterogeneity. CCR2⁻ monocytes rely on CCR5 for entry, whereas CCR2⁺ monocytes require both CCR2 and CX3CR1. This suggests that CX3CR1 is crucial for CCR2⁺ monocyte recruitment to plaques, unlike in other inflammatory settings where CCR2 is sufficient. Targeting CX3CR1 may be effective in reducing atherosclerosis without impairing CCR2-dependent inflammatory responses. The study used latex bead labeling to trace monocyte subsets and their differentiation in plaques, revealing that CCR2⁺ monocytes use CCR2 and CX3CR1, while CCR2⁻ monocytes rely on CCR5. These findings highlight the distinct roles of chemokine receptors in monocyte recruitment and plaque development, with implications for therapeutic strategies targeting atherosclerosis.