Therapeutic reversal of immune tolerance following immune checkpoint inhibitors (ICPI) administration, has proven effective in prolonging survival of patients with a variety of solid and liquid tumors, often however at the expenses of discrete toxicities known as immune-related adverse events (AEs). Such reactions result from activation of the immune system and often present with generalized symptoms including fatigue or fever and, in some patients, may cause organ-specific damage. Skin, gut, endocrine, lung and musculoskeletal are the most frequent targets of ICPI toxicity whereas, cardiovascular, hematologic, renal, neurologic and ophthalmologic AEs occur much less frequently. While the majority of AEs are mild to moderate, serious, occasionally life-threatening reactions have been reported, including severe colitis, pneumonitis, encephalitis, toxic epidermal necrolysis, myocarditis, and diabetic ketoacidosis, with a death toll of 2%. Hepatocellular carcinoma (HCC) is becoming an attractive area for immunotherapy. Owing to the fact that the association of HCC with cirrhosis may jeopardize tolerability of ICPI therapy, attention has been paid to identifying, preventing, and treating the AEs associated with ICPI, with a focus on liver safety. Though in most studies AEs resolved with interruption of treatment and short course of steroids, identification of predictive biomarkers of response might help sparing patients from potentially life-threatening toxicity in the absence of clinical benefit.