Lenalidomide (LEN) is an immunomodulatory drug with US Food and Drug Administration approval for use in myelodysplastic syndromes (MDS), multiple myeloma (MM), and mantle cell lymphoma (MCL). The toxicity profile for LEN is similar across indications, with the most common adverse events reported in registration trials being hematologic in nature, and Grade ≥ 3 hematologic toxicities the most common reasons for treatment interruption or permanent LEN discontinuation. However, an analysis of the Celgene Global Drug Safety database showed that nonserious rash was the leading cause of permanent early discontinuation of LEN in patients with MDS treated in the postmarketing setting (similar data not available for patients with MM or MCL). In registration trials, rash was reported in up to a third of patients, but Grade ≥ 3 rash was uncommon and rash rarely led to LEN treatment interruption or permanent discontinuation. This suggests differences in management of LEN-related rash in clinical trials versus real-world use. Most LEN-related rash is mild to moderate in severity and might present as patchy, raised, macular skin lesions, sometimes with localized urticaria, which might be associated with pruritus. Mild to moderate rash might be treated with topical corticosteroids and/or oral antihistamines. Any grade LEN-related rash should be appropriately managed through awareness of symptoms, appropriate and prompt intervention, and maximizing patient self-reporting of early signs of rash using upfront educational initiatives. This guide to management of LEN-related rash reviews key clinical data from registration trials, and the incidence and physiology of LEN-related rash, grading of rash, and guidelines for patients and caregivers.