The historical legacy of Eastern European and the Balkans’ health systems was mutually interdependent and shaped by local socioeconomic circumstances. Three distinctive systems of risk sharing and health financing developed since the late XIX century were the Bismarck, Beveridge, and Semashko systems. Modern day healthcare systems in these countries are challenged by population aging, accelerated innovation in medical technology, growing purchasing power and rising demand for healthcare services. Supply-side changes contribute to demand-side efficiency bottlenecks in financing, driving up the costs of the already expensive medical care. All of the nations have a large share of citizens experiencing difficulty with affordability and access to medical care, particularly in rural and remote areas. Network of health technology assessment agencies have mushroomed over the past three decades. Principles of health economics theory and cost-effective resource allocation are slowly gaining ground in governing authorities’ mindset and decision-making processes. For many years to come, pharmaceuticals and medical services will remain dependent on out-of-pocket spending. Currently, accelerating and spreading 4.0 Industrial Revolution, together with the Belt and Road Initiative, are likely to substantially impact the further economic development of this vast region. Post-pandemic “green” recovery strategies adopted by many of the Eastern European governments shall also make this transition toward sustainable development more difficult and challenging, given the large dependency of all these economies on traditional carbon fuels.