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Tail-anchored proteins (TAPs) are a subclass of type II integral membrane proteins that carry out important and diverse functions within cells. Structurally, TAPs present an N-terminal domain exposed to the cytosol and a single transmembrane domain (TMD) close to the C-terminus, the latter is responsible for the targeting and insertion into the proper intracellular membrane (endoplasmic reticulum (ER), mitochondria, peroxisomes). Due to this particular topology, TAPs insert obligatorily into membranes by post-translational pathways and are excluded from the classical SRP dependent co-translational ER insertion. ER-targeted TAPs can follow two distinct ways of insertion according to the hydrophobicity of their TMD. In the "assisted" pathway, TAPs with more hydrophobic TMDs insert in the ER membrane with the requirement of energy and the involvement of proteinaceous component(s). By contrast neither energy, nor membrane or cytosolic proteins are necessary and do not even improve the "unassisted" insertion of TAPs with moderately hydrophobic TMDs. In this review, we discuss the most relevant recent data regarding the molecular mechanism that underlies these processes.