Myeloproliferative neoplasms (MPNs) include essential thrombocythemia, 
polycythemia vera (PV), and primary myelofibrosis (MF). Phenotype-driver 
mutations of JAK2, CALR, and MPL genes are present in MPNs and can be variably 
combined with additional mutations. Driver mutations entail a constitutive 
activation of the JAK2/STAT pathway, the key signaling cascade in MPNs. Among 
JAK2 inhibitors (JAKis), ruxolitinib (RUX) has been approved for the treatment 
of intermediate and high-risk MF and for PV inadequately controlled by or 
intolerant of hydroxyurea. Other JAKis, such as fedratinib and pacritinib, 
proved to be useful in MF. The primary end points in MF trials were spleen 
volume response (SVR) and symptom response, whereas in PV trials they were 
hematocrit control with or without spleen response. In advanced MF, RUX achieved 
a long lasting SVR of >35% in ∼60% of patients, establishing a new benchmark for 
MF treatment. RUX efficacy in early MF is also remarkable and toxicity is mild. 
In PV, RUX achieved hematocrit control in ∼60% of cases and SVR in 40%. Symptom 
relief was evident in both conditions. In the long-term, however, many MF 
patients lose their SVR. Indeed, the definition of RUX failure and the design of 
new trials in this setting are unmet needs. Decrease of hemoglobin/platelet 
levels and increased infection rates are the most common side effects of RUX, 
and nonmelanoma skin tumors need to be monitored while on treatment. In 
conclusion, the introduction of JAKis raises the bar of treatment goals in MF 
and PV.