Over the last two decades, the safety and acceptability of antidepressants have been enhanced considerably. However, the adverse effects due to antidepressants are still challenging. Majority of the antidepressants cause annoying side effects when prescribed to patients with depression. These side effects often form hurdles to achieving remission of depressive episodes. Quite often the frequency of side effects are underestimated and nearly 25% of patients discontinue their treatment because of hard-to-accept adverse effects; others may continue on medication but experience reduced quality of life due to worrying adverse effects. Proper controlling of adverse effects improves adherence, warrants suitable dosing, increases patient well-being and stops early termination of therapy. Suitable management comprises thoughtful drug assortment, expectation of common and rare but serious adverse effects and attempting for the lowest effective dose and simplest drug schedules reliable with appropriately robust management.