High rates of resource consumption and waste generation have put pressure on environmental systems and one of the solutions to this concerning behavior is a circular bioeconomy (CBE). However, for a CBE to succeed, new businesses and business models are needed, for which many drawbacks might be faced. Therefore, this article aimed (i) to identify the drivers, opportunities, challenges, and barriers for businesses in a CBE both from theoretical and practical perspectives, and (ii) to present the regional differences in those aspects for different continents. A mixed-method approach was adopted, comprising a systematic literature review and semi-structured interviews with 32 organizations from 18 countries in 4 continents (Africa, America, Australia, and Europe). Eight barriers and twenty challenges, as well as fifteen drivers and eight opportunities were identified. The main barrier and challenge pointed out by stakeholders were lack of financial resources/capital, and price competitiveness with traditional/linear product offers. The most prominent driver and opportunity were establishment of public policies/governmental support, and waste recovery. Regional aspects of CBEs (by continent) were also identified. Advancing CBEs requires setting strategies to overcome the lack of financial resources/capital, developing and/or making the adequate technology available locally, and enabling price competitiveness with traditional (linear and non-renewable-based) options. This study also unveils a series of managerial and business implications. There is the risk of rebound effects, such as waste becoming mainstream feedstock and bioproducts being introduced to the market on low-price strategies, thus triggering increased consumption. Premium pricing strategies need to be considered for bio-based products (compared with non-bio-based products). Moreover, technological development plays a role in driving innovation, and pioneers might lead the development of policies. For CBE systems to succeed there needs to be further technological development and greater connection among the actors in the value chain, converging in resilient circular business models for a CBE.