Citrus is an economically important fruit crop that is seriously afflicted by several biotic stress, caused by both viruses and fungi, thus, new sustainable strategies to manage these diseases are needed. Lemon (Citrus limon (L.) Burm. f) is a tree in the Rutaceae family and after orange and mandarin, is the third most important Citrus species. Lemon fruits contain important bio-compounds and have central role in prevention of diseases of a balanced diet. Among C. limon diseases, "mal secco" is a highly destructive tracheomycotic fungal infection spread over the coasts of the Mediterranean basin and the Black Sea areas. The causal agent is the mitosporic fungus Phoma tracheiphila (Petri) Kantschaveli & Gikachvili (syn. Deuterophoma tracheiphila Petri). The pressure of disease has led to a marked decline of the Mediterranean's lemon crop acreage in the last 30 years. The present review explores the state of art in the struggle against mal secco disease (MSD), summarizing main results obtained from both conventional and unconventional breeding approaches. In addition, the strategies used to study the mechanisms involved in P. tracheiphila/lemon interaction and the results obtained to isolate key genes activates in tolerant genotypes are also described in depth. The overview of emergent approaches and technologies is focused to highlight the progress obtained using advanced lemon-breeding methods and suggest guidelines for future research.