Tau aggregation modulators represent a promising therapeutic approach for addressing tauopathies, including Alzheimer’s disease (AD) and other neurodegenerative disorders characterized by accumulation of pathological tau assemblies. Tau, a microtubule-associated protein, undergoes aberrant posttranslational modifications (PTMs) under disease conditions. As a result, tau’s normal cellular localization and function are disrupted, leading to the formation of toxic oligomers and insoluble aggregated forms, such as neurofibrillary tangles, which deposit in neurons and glia and correlate with disease severity and progression. Various tau modulators, including small molecules, peptides, and antibodies, have been tested in preclinical experiments and clinical trials. In addition to direct modulators, phosphorylation inhibitors, which target tau aggregation by reducing the hyperphosphorylation that correlates with aggregation, have been tested as potential therapeutic agents, yet to date, none of the attempts have resulted in approved therapy. Moreover, except for the recently approved anti-amyloid antibodies, lecanemab and donanemab for AD, there are no disease-modifying treatments for tauopathies, making development of new therapies an urgent, unmet public health need. Here, we discuss primarily the in vivo results obtained for tau-assembly modulators belonging to different chemical families, including those that have reached clinical trials, compounds still in preclinical development, and recent approaches creating and developing such compounds for treatment of tauopathy.