The growing interest in processes that involve biomass conversion to renewable energy, such as anaerobic digestion, has stimulated research in this field in order to assess the optimum conditions for biogas production from abundant feedstocks, like agro-industrial wastes. Anaerobic digestion is an attractive process for the decomposition of organic wastes via a complex microbial consortium and subsequent conversion of metabolic intermediates to hydrogen and methane. The present study focused on the exploitation of liquid cow manure (LCM) and cheese whey (CW) as noneasily and easily biodegradable sources, respectively, using continuous stirred-tank reactors for biogas production, and a comparison was presented between single- and two-stage anaerobic digestion systems. No significant differences were found concerning LCM treatment, in a two-stage system compared to a single one, concluding that LCM can be treated by implementing a single-stage process, as a recalcitrant substrate, with the greatest methane production rate of 0.67 L CH4/(LR·d) at an HRT of 16 d. On the other hand, using the easily biodegradable CW as a monosubstrate, the two-stage process was considered a better treatment system compared to a single one. During the single-stage process, operational problems were observed due to the limited buffering capacity of CW. However, the two-stage anaerobic digestion of CW produced a stable methane production rate of 0.68 L CH4/(LR·d) or 13.7 L CH4/Lfeed, while the total COD was removed by 76%.