MicroRNAs (miRNAs) are recognized as an emerging class of master regulators that regulate human gene expression at the post-transcriptional level and are involved in many normal and pathological cellular processes. Mammalian basic HLH (helix-loop-helix)-PER-ARNT-SIM (bHLH-PAS) proteins are heterodimeric transcriptional regulators that sense and respond to environmental signals (such as chemical pollutants) or to physiological signals (for instance hypoxia). In the normal state, bHLH-PAS proteins are responsible for multiple critical aspects of physiology to ensure the cell accurate homeostasis, but dysregulation of these proteins has been shown to contribute to carcinogenic events such as tumor initiation, promotion, and progression. Increasing epidemiological and experimental studies have shown that bHLH-PAS proteins regulate a panel of miRNAs, whereas some miRNAs also target bHLH-PAS proteins. The interaction between miRNAs and certain bHLH-PAS proteins [hypoxia-inducible factor (HIF) and aryl hydrocarbon receptor (AHR)] is relevant to many vital events associated with tumorigenesis. This review will summarize recent findings on the interesting and complicated underlying mechanisms that miRNAs interact with HIFs or AHR in tumors, hopefully to benefit the discovery of novel drug-interfering targets for cancer therapy.