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1, 2, 3 This cellular balance is often referred to as a ‘yin-yang’ and unobstructed cellular functions are only achievable when harmonious. Homeostasis relies on a balance between de novo protein synthesis, protein modifications, and precise degradation of misfolded and potentially harmful proteins. In addition, our review highlights potential areas for future research on SIAH proteins. We also discuss that epigenetic drugs belonging to the group of histone deacetylase inhibitors induce SIAH-dependent proteasomal degradation to accelerate the turnover of leukemogenic proteins. Here, we summarize functions of SIAH ubiquitin-ligases in leukemias, how they select leukemia-relevant substrates for proteasomal degradation, and how the expression and activity of SIAH1 and SIAH2 can be modulated in vivo. However, the relevance and therapeutic potential of SIAH-dependent processes has not been fully elucidated. Increasing evidence accumulates that ubiquitin-ligases termed mammalian seven in absentia homologs (SIAHs) are not only critical for the pathogenesis of solid tumors but also for leukemogenesis. Therefore, pharmacological modulation of these proteins could allow a specific level of control. Ubiquitin-ligases selectively bind substrates to target them for poly-ubiquitinylation and proteasomal degradation. As dysregulation of the UPS is observed in most cancers including leukemia, the UPS is a valid target for therapeutic intervention strategies. The ubiquitin–proteasome system (UPS) is a major pathway for the proteolytic degradation of cellular proteins. Proteases act in an irreversible manner and therefore have to be strictly regulated. The delicate balance between the synthesis and the degradation of proteins ensures cellular homeostasis.