The human-derived SH-SY5Y neuroblastoma cell line is widely used for studying TAU physiology and TAU-related pathology in Alzheimer’s disease (AD) and related tauopathies. SH-SY5Y cells can be differentiated into neuron-like cells (SH-SY5Y-derived neurons), which resemble noradrenergic, dopaminergic or cholinergic neurons, by using various substances. This review evaluates whether SH-SY5Y-derived neurons are a suitable model for investigating intracellular TAU sorting mechanisms in general, and with respect to neuron subtype-specific TAU vulnerability. SH-SY5Y-derived neurons show pronounced axodendritic polarity resembling neuronal cell polarity, high TAU protein levels, axonal TAU localization, expression of the six major human brain isoforms, and TAU phosphorylation similar to AD. This enables studying the isoform- and phosphorylation-dependent impact on TAU subcellular distribution and axodendritic trafficking of TAU. As SH-SY5Y cells are accessible for genetic engineering, stable transgene integration and leading-edge genome editing are valuable and often-used tools for TAU-related research in these cells. Furthermore, SH-SY5Y-derived neurons resemble cells of distinct subcortical nuclei, i.e. the Locus coeruleus (LC), Nucleus basalis (NB) and Substantia nigra (SN), depending on the used differentiation procedure. This allows to study neuron-specific TAU isoform expression and intracellular localization in the context of vulnerability to TAU pathology. Limitations are e.g. the lack of mimicking age-related tauopathy risk factors and the difficulty to define the exact neuronal subtype of SH-SY5Y-derived neurons. In brief, this review discusses the suitability of SH-SY5Y-derived neurons for investigating TAU sorting mechanisms and neuron-specific TAU vulnerability in human-like conditions.