This mini review intends to highlight the importance of bilayer asymmetry. Biological membranes are complex structures that are a physical barrier separating the external environment from the cellular content. This complex bilayer comprises an extensive lipid repertory, suggesting that the different lipid structures might subserve a role in the membrane. Interestingly, this vast repertory of lipids is asymmetrically distributed between leaflets that form the lipid bilayer. Here, we discuss the properties of the plasma membrane under the view of experimental model membranes, consisting in simplified and controlled in vitro systems. We summarize some crucial features of the exoplasmic (outer) and cytoplasmic (inner) leaflets observed through investigations using symmetric and asymmetric membranes. Symmetric model membranes for the exoplasmic leaflet have a unique lipid composition that might form a coexistence of phases, namely liquid disordered and liquid order phases. These phase domains may appear in different sizes and shapes depending on lipid composition and lipid-lipid interactions. In contrast, symmetric model membranes for the cytoplasmic leaflet form a fluid phase. We discuss the outcomes reported in the literature for asymmetric bilayers, which vary according to lipid compositions and, consequently, reflect to different intra- and inter-leaflet interactions. Interestingly, the asymmetric bilayer could show induced domains in the inner leaflet, or it could decrease the tendency of the outer leaflet to phase separation. If cells regulate the lipid composition of the plasma membrane, they can adjust the existence and sizes of the domains by tuning the lipid composition.