Reverse cholesterol transport (RCT) has been characterized as a crucial step for anti-atherosclerosis, which is initiated by ATP-binding cassette A1 (ABCA1) to mediate the efflux of cellular phospholipids and cholesterol to lipid-free apolipoprotein A-I (apoA-I), however, the mechanisms underlying apoA-I/ABCA1 interaction to lead to the lipidation of apoA-I are poorly understood. There are several models proposed for the interaction of apoA-I with ABCA1 as well as lipidation of apoA-I mediated by ABCA1. ApoA-I markedly increases the levels of ABCA1 protein, ABCA1 inturn can stabilize apoA-I. The interaction of apoA-I with ABCA1 could activate signaling molecules that modulate post-translational ABCA1 activity or lipid transport activity. The key signaling molecules in these process include protein kinase A (PKA), protein kinase C (PKC), Janus kinase 2 (JAK2), Rho GTPases and Ca(2+), and many factors could also influence the interaction of apoA-I with ABCA1. This review will summarize these mechanisms for the apoA-I interaction with ABCA1 as well as the signal transduction pathways involved in these process.