In sweet cherry (Prunus avium L.), flowering date is strongly dependent on the environment conditions and, therefore, is a trait of major interest for adaptation to climate change. Such trait can be influenced by genotype-by-environment interaction (G×E), that refers to differences in the response of genotypes to different environments. If not taken into account, G×E can reduce selection accuracy and overall genetic gain. However, little is known about G×E in fruit tree species. Flowering date is a highly heritable and polygenic trait for which many quantitative trait loci (QTLs) have been identified. As for the overall genetic performance, differential expression of QTLs in response to environment (QTL-by-environment interaction, QTL×E) can occur. The present study is based on the analysis of a multi-environment trial (MET) suitable for the study of G×E and QTL×E in sweet cherry. It consists of a sweet cherry F1 full-sib family (n = 121) derived from the cross between cultivars 'Regina' and 'Lapins' and planted in two copies in five locations across four European countries (France, Italy, Slovenia and Spain) covering a large range of climatic conditions. The aim of this work was to study the effect of the environment on flowering date and estimate G×E, to carry QTL detection in different environments in order to study the QTL stability across environments and to estimate QTL×E. A strong effect of the environment on flowering date and its genetic control was highlighted. Two large-effect and environment-specific QTLs with significant QTL×E were identified on linkage groups (LGs) 1 and 4. This work gives new insights into the effect of the environment on a trait of main importance in one of the most economically important fruit crops in temperate regions. Moreover, molecular markers were developed for flowering date and a strategy consisting in using specific markers for warm or cold regions was proposed to optimize marker-assisted selection (MAS) in sweet cherry breeding programs.