Molecular biology and physiology studies have led to a better understanding of Hevea biological functions. Thanks to biotechnology and new generation of sequencing techniques, some applications are available for breeding and clonal propagation. This paper aims to discuss the relevance of these research activities with regard to the main issues and challenges for natural rubber production. Sustainable rubber production is facing challenges towards adaptation to climate change and overcome environmental degradation. Objectives of the Climate-Smart Agriculture should deal with integration of agro-ecology and management of both Hevea genetic resources and ecosystem services provided by rubber plantations. Inputs of molecular biology and physiology are reviewed in this paper in order to highlight crucial issues for accelerating and optimizing the conservation of Hevea genetic resources, adaptation of Hevea clones to abiotic and biotic stress, improvement of the quality of planting material, production of a higher quality of NR and new latex products, and assessment of plantation biodiversity and ecosystem functions.