This article provides a brief review of macroprolactin (MPRL) – what, why, how, and when. Prolactin (PRL) secretion is uniquely controlled by tonic dopamine inhibition. Circulating PRL is a heterogeneous mixture of different sized proteins – monomer, dimer, and a large PRL-immunoglobulin aggregate also known as MPRL. Hyperprolactinemia (HPRL), which affects male sexual function and female reproduction, is a common endocrine disorder. Elevated PRL may be physiologic, pharmacologic, or pathologic. However, MPRL is quite common (ranging from 13–30%) and should be excluded before inappropriate investigations and therapy for HPRL are initiated. MPRL can be precipitated by mixing serum with polyethylene glycol (PEG) followed by centrifugation; monomeric PRL remains in the supernatant. MPRL is considered present if the PRL recovery is less than 40% or if the post-precipitation PRL concentration is low. The use of both measures for MPRL provides greater clarity. Different immunoassay platforms recognize MPRL differently necessitating assay-specific reference ranges. All HPRL samples should be screened for MPRL.