Recent advances in CRISPR/Cas-based epigenome editing technologies have enabled programmable control over human gene expression, chromatin states, and genomic organization. Consequently, these emerging technologies have created new opportunities to engineer human cells for therapeutic benefit and catalyzed innovative ways to functionally interrogate gene regulatory mechanisms in situ. Toward these ends, we have recently developed new capabilities in the context of CRISPR/Cas-based transcriptional activation (CRISPRa) modalities. First, we have identified and repurposed key segments from natural human transcription factors to build potent and compact multipartite transactivation modules and in turn build the CRISPR-DREAM platform. CRISPR-DREAM is specific, robust across mammalian cell types, efficacious at diverse human regulatory elements, and well tolerated in therapeutically important primary cells – including T cells, MSCs, neurons, and iPSCs. We have also leveraged the small size and potency of CRISPR-DREAM components to generate all-in-one CRISPRa AAV systems that expand opportunities for in vivo gene control. Second, in unpublished studies, we have isolated intrinsically disordered regions (IDRs) from oncogenic fusion proteins associated with therapeutically intractable hematologic malignancies and nuclear phase separation. We find that different IDR compositions exhibit distinct propensities for nuclear import and biomolecular condensation in human cell nuclei. We demonstrate using precision CRISPR-based targeting of IDRs to human loci, that levels of phase separation can be directly proportional to target gene activation. Interestingly we also find that while core transcriptomic network changes are shared among certain oncogenic IDR fusion proteins, phase separation behaviors and genomic engagement occur in discrete ways – suggesting divergent IDR-driven routes to cellular oncogenesis, the control over which could create new possibilities for tailored therapeutic approaches.