Acromegaly is a chronic disease with an increased mortality in case of persistently active disease. The treatment of acromegaly is mainly based on the surgical resection of the GH secreting pituitary tumor and, in cases with persistent disease, on the medical therapy with first generation somatostatin analogues (first gen-SSAs). Data from national registries, meta-analysis and epidemiology studies showed that 24%-65% of acromegaly patients treated with first gen-SSA did not reach the control of disease, requiring second line therapies, as the second gen-SSAs and the GH receptor antagonist. According to the high efficacy of these treatments and their molecular mechanisms of action, the choice of second line therapies should be personalized. In this review, we summarize the evidence on clinical, molecular and morphological aspects that may predict the response to second line therapies, in order to integrate and translate in the clinical practice for a patient-tailored therapeutic approach.