Nuclear receptor modulation enables pharmacological control of gene expression thus rendering the 48 human nuclear receptors as attractive targets for drug discovery. Several nuclear receptor ligands like glucocorticoids are approved and highly important drugs illustrating the therapeutic potential of nuclear receptor modulation. However, a significant portion of the nuclear receptor family is still poorly explored for new therapeutic opportunities which is due to a lack of potent, selective and well-characterized ligands. Preliminary evidence supports great therapeutic potential of several orphan nuclear receptors in various pathologies underlining the need for high-quality chemical tools to enable target validation. Here, we evaluate the characteristics of available nuclear receptor modulators and the gaps in coverage of the nuclear receptor family with chemical tools. We review successful approaches to nuclear receptor modulator development and highlight the opportunities and challenges in closing the gaps of missing tools for understudied nuclear receptors to open new therapeutic avenues.