During the last decades, emerging evidence has shown that atherosclerosis is characterised by a complex endocrine, paracrine and juxtacrine cross-talk between immune and vascular cells as well as several tissues and organs, including the liver, heart, kidney, adipose tissue, adrenal, pancreatic, pituitary and sex glands [1]. Thus, atherosclerosis has to be considered as a “systemic disease”, characterised by arterial inflammatory lesions that mature and modify themselves with disease progression. Atherosclerotic plaques are the battlefield among an unbalanced immune response and lipid accumulation in the intima of arteries. Although the “first event” favouring early lipid deposition within the arterial sub-intimal space has not been identified, the infiltration of low-density lipoproteins (LDL) should be considered as the pivotal step in plaque formation [2]. Oxidative and enzymatic modifications of retained LDL increase the expression of adhesion molecules on endothelial cell surface membrane, thus favouring leukocyte recruitment from the blood stream [3]. Leukocytes recruitment within atherosclerotic plaques is also orchestrated by the chemokine binding to their receptors on cell membrane. This is a redundant system which regulates all inflammatory phases of atherogenesis in both humans and animals [4]. Monocytes have been defined by Weber et al. as the “crucial force” to drive atherogenesis [3]. In vivo monocyte inflammatory functions and differentiation are influenced by the different expression of chemokine receptors, CD14 and CD16. Two different monocyte subsets have been identified. Inflammatory monocyte subset (CXC3CR1 CCR2Ly6CCD14CD16) represents the main population recruited within the plaque from the blood stream and display both phagocytic and proteolytic activities. On the other hand, resident monocyte subset (CXC3CR1 CCR2Ly6CCD14CD16) is the main population involved in the initiation of tissue inflammation, angiogenesis and atheroprogression [3]. Modified LDL are uptaked by scavenger receptors of resident macrophages that differentiate into different inflammatory cell types, such as dendritic cells, foam cells, osteoclastand osteoblast-like cells. These processes are modulated by several cytokines and growth factors (such as receptor activator of nuclear factor [NF]kappaB ligand [RANKL], osteoprotegerin [OPG], tumour necrosis factor [TNF]alpha, granulocyte macrophage-colony stimulating factor [GM-CSF], macrophage-colony-stimulating factor [MCSF] and interleukin [IL]-4). On the other hand, connexins, which mediate gap junction formation between adjacent cells (vascular and immune cells), have been recently shown to playing a crucial role in cell differentiation and growth. Three different connexins (Cx37, Cx40 and Cx43) are differently expressed in macrophage and endothelial cells during atherosclerotic plaque maturation [5]. At this step, the non-specific immune response, mainly characterised by local monocyte/macrophage-mediated inflammatory processes has started. In a second phase, resident inflammatory and vascular cells further produce chemokines for the recruitment of T lymphocytes within the plaque. This induces the deleterious vicious circle of the Semin Immunopathol (2009) 31:1–3 DOI 10.1007/s00281-009-0146-7