Evolutionary processes and acquired tolerance to toxicants are important factors governing how animals respond to chemical exposure. Evidence for increased tolerance to cadmium (Cd), a widely distributed toxic metal in aquatic environments, in Chironomus riparius is conflicting and still questioned if it happens through phenotypic plasticity or genetic adaptation. The present study considered the relevance of directional environmental changes by increasing contaminant concentration in a multigenerational selection experiment. Evaluation of measurable life-cycle traits, transcriptomic responses and quantitative genetics from an evolve and resequencing (E&R) experiment were integrated to assess the potential of C. riparius to adapt to Cd. Survival tests revealed some adaptation to Cd exposure. Genomic analyses showed a strong, genome-wide selective response in all replicates, emphasizing that even control laboratory conditions continually exert selective pressure. The integration of transcriptomic and genomic data could isolate the genes related to Cd acquired resistance. Those genes could be linked to an efflux of metals. Therefore, it is possible to conclude that C. riparius can endure long-term Cd exposure also through genetic adaptation.