Cellular organelles that lack a surrounding lipid bilayer, such as the nucleolus and stress granule, represent a newly recognized, general paradigm of cellular organization. The formation of such biomolecular condensates that include ‘membraneless organelles’ (MLOs) by liquid–liquid phase separation (LLPS) has been in the focus of a surge of recent studies. Through a combination of in vitro and in vivo approaches, thousands of potential phase-separating proteins have been identified, and it was found that different cellular MLOs share many common components. These perplexing observations raise the question of how cells regulate the timing and specificity of LLPS, and ensure that different MLOs form and disperse at the right moment and cellular location and can preserve their identity and physical separation. This guide gives an overview of basic regulatory mechanisms, which manifest through the action of intrinsic regulatory elements, alternative splicing, post-translational modifications, and a broad range of phase-separating partners. We also elaborate on the cellular integration of these different mechanisms and highlight how complex regulation can orchestrate the parallel functioning of a dozen or so different MLOs in the cell.
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