Numerous epidemiologic studies revealed that high-density lipoprotein (HDL) is an important risk factor for coronary heart disease. There are several well-documented HDL functions such as reversed cholesterol transport, inhibition of inflammation, or inhibition of platelet activation that may account for the atheroprotective effects of this lipoprotein. Mechanistically, these functions are carried out by a direct interaction of HDL particle or its components with receptors localized on the cell surface followed by generation of intracellular signals. Several HDL-associated receptor ligands such as apolipoprotein A-I (apoA-I) or sphingosine-1-phosphate (S1P) have been identified in addition to HDL holoparticles, which interact with surface receptors such as ATP-binding cassette transporter A1 (ABCA1); S1P receptor types 1, 2, and 3 (S1P1, S1P2, and S1P3); or scavenger receptor type I (SR-BI) and activate intracellular signaling cascades encompassing kinases, phospholipases, trimeric and small G-proteins, and cytoskeletal proteins such as actin or junctional protein such as connexin43. In addition, depletion of plasma cell cholesterol mediated by ABCA1, ATP-binding cassette transporter G1 (ABCG1), or SR-BI was demonstrated to indirectly inhibit signaling over proinflammatory or proliferation-stimulating receptors such as Toll-like or growth factor receptors. The present review summarizes the current knowledge regarding the HDL-induced signal transduction and its relevance to athero- and cardioprotective effects as well as other physiological effects exerted by HDL.