Competitive endogenous (ce)RNAs cross-regulate each other through sequestration of shared microRNAs and form complex regulatory networks based on their microRNA signature. However, the molecular requirements for ceRNA cross-regulation and the extent of ceRNA networks remain unknown. Here, we present a mathematical mass-action model to determine the optimal conditions for ceRNA activity in silico . This model was validated using phosphatase and tensin homolog (PTEN) and its ceRNA VAMP (vesicle-associated membrane protein)-associated protein A (VAPA) as paradigmatic examples. A computational assessment of the complexity of ceRNA networks revealed that transcription factor and ceRNA networks are intimately intertwined. Notably, we found that ceRNA networks are responsive to transcription factor up-regulation or their aberrant expression in cancer. Thus, given optimal molecular conditions, alterations of one ceRNA can have striking effects on integrated ceRNA and transcriptional networks.