The nucleolar stress response, an important mechanism in the maintenance of cellular integrity, has been implicated in human diseases, particularly in cancer and diseases of the ribosome (ribosomopathies). It is known that perturbations in ribosome biogenesis can activate the nucleolar stress response, where free ribosomal proteins (RPL5 and RPL11) bind to MDM2, leading to the stabilisation of p53. However, the detailed molecular mechanism underlying this process is still unclear. We performed a functional genome-wide loss of function (RNAi) screen to identify novel modulators of the p53-mediated nucleolar stress response that is activated due to ribosomal protein insufficiency. Validation of the screening data yielded high and medium confidence candidates; these were further validated using in vitro assays. A number of our high confidence candidates block p53 stabilisation induced by RPS19 knockdown and by nucleolar stress-inducing agents, CX-5461 and Leptomycin B, while a number also enhance p53 stabilisation, which could be utilised for the enhanced treatment of cancer. Overall, these candidates may be able to be targeted therapeutically (i.e the target is blocked or its activity enhanced, depending on the disease) for the treatment of a variety of diseases where the nucleolar stress response is involved, including cancers and ribosomopathies.