Circadian rhythms—daily cycles that regulate behavior, physiology, and mental state—are influenced by environmental cues such as light cycles and food intake. Misalignment between an organism’s internal clock and its environment, as seen in night shift workers, is associated with an increased risk of specific types of cancer. Moreover, many tumors display disrupted co-expression of clock genes relative to healthy tissue of the same origin. This suggests that circadian disruption not only enhances malignancy risk, but it also serves as a hallmark of disease pathology. However, the effect of circadian disruption on cancer growth and the degree to which tumors have disrupted expression of clock genes is not universal and is likely influenced by several factors such as tissue origin and molecular mechanisms driving disease progression. Genetically engineered mouse models (GEMMs) of cancer housed in lighting conditions that mimic the disruption experienced in night shift workers demonstrate enhanced tumor burden in some cases, but this is not observed in all GEMMs, such as in the case of c-MYC driven lymphoma. This suggests that each cancer type should be considered separately when assessing the impact of circadian disruption on tumorigenesis. In addition to manipulating lighting schedules, genetic deletion of the circadian clock transcription factor, brain and muscle ARNT-like protein 1 (BMAL1), in the background of GEMMs of malignancy has been shown to exacerbate or improve the disease outcome depending on the type of cancer being investigated. This paradoxical effect suggests that the relationship between the circadian clock components and cancer is also highly context-dependent and influenced by specific genetic and environmental factors. Clear cell renal cell carcinoma (ccRCC) is characterized by inactivation of the von Hippel Lindau (VHL) ubiquitin ligase, which targets hypoxia inducible factors 1 alpha (HIF1α) and 2 alpha (HIF2α, a.k.a. EPAS1) for degradation. Like BMAL1, HIF1α and HIF2α are basic helix-loop-helix and PERARNT-SIM domain (bHLH-PAS) transcription factors that bind DNA with a common heterodimer partner aryl hydrocarbon receptor nuclear translocator (ARNT, a.k.a., HIF1β). Suppression of HIF2α is 2 required for VHL to inhibit ccRCC tumor growth (Courtney et al., 2020; Kondo et al., 2002), highlighting the oncogenic role of HIF2α in ccRCC. Here, we found ccRCC exhibits robust circadian rhythms and clinical samples of ccRCC have higher BMAL1 expression and percentage of BMAL1 positive nuclei relative to normal kidney tissue. BMAL1 cooperates with HIF2α to activate transcription. While BMAL1 depletion reprograms HIF2α chromatin association and HIF2α target gene expression and reduces ccRCC growth in culture and in xenografts. BMAL1 overexpression drives tumorgraft growth via interactions with HIF2α. These findings suggest a critical role for BMAL1 in ccRCC. Considering the critical function of HIF2α driving ccRCC growth, significant efforts have been made to develop small molecules that disrupt HIF2α-ARNT heterodimers. In 2021, the FDA approved belzutifan for treating VHL-mutated ccRCC patients. Despite this milestone, approximately 30% of ccRCC patient-derived xenografts (PDXs) exhibit resistance to HIF2α antagonists like PT2399. RNAsequencing analysis of these PDXs revealed that BMAL1 mRNA levels were higher in tumors sensitive to HIF2α antagonists, suggesting BMAL1 may influence treatment responsiveness. Supporting this, BMAL1-HIF2α heterodimers are more susceptible to PT2399-mediated suppression than ARNT-HIF2α heterodimers. Additionally, ccRCC tumorgrafts expressing mutant BMAL1, which cannot bind HIF2α, are resistant to PT2399-induced growth suppression. Notably, the efficacy of PT2399 in suppressing tumor growth depends on the time of day it is administered, emphasizing the circadian influence on treatment. These findings suggest that an alternative HIF2α heterodimer—incorporating BMAL1— modulates HIF2α activity, tumor growth, and drug sensitivity in ccRCC. This underscores the need to consider the circadian-hypoxia axis when optimizing belzutifan therapy in clinical settings and presents alternative targets for future therapeutic approaches.