Lithuania, like all other European Union Member States has to meet the Smart Specialization Strategy (RIS3) ex-ante conditionality for the 2014-2020 Structural Funds (SF) programming period. According to the Smart Specialisation platform, RIS3 is a regional strategic approach to economic development through targeted support to Research and Innovation. However, Lithuania being the seventh smallest country in the EU is considered as one region in the SF programming map, so RIS3 preparation is an opportunity to evaluate the resources and potential of the whole country. Moreover, this is a chance to adopt a new approach to the strategic support for science and business collaboration in order to exploit the possibilities of the current potential. This article reflects main provisions of the RIS3 preparation for Lithuania and briefly presents the experience and achievements so far.