Following the approval of Epidiolex® (cannabidiol; CBD) for the treatment of seizures associated with Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and tuberous sclerosis complex (TSC), healthcare professionals (HCPs) have had substantial experience in treating patients with Epidiolex. However, confusion still remains among HCPs, caregivers, and patients regarding dosing, drug interactions, safety monitoring, and differentiation between Epidiolex and nonapproved CBD products. To establish consensus recommendations for Epidiolex treatment optimization in LGS, DS, and TSC, a panel of seven HCPs with expertise in epilepsy was convened. Panelists participated in a premeeting survey based on a literature review of Epidiolex for the treatment of LGS, DS, and TSC, and survey responses were compiled for discussion. A modified Delphi method was used to assess agreement among panelists regarding recommendation statements following two rounds of discussion. Panelists identified two broad themes - overcoming barriers to initiation and optimization of treatment for seizures associated with LGS, DS, and TSC - for consensus guidelines. Accurate identification of patients with these rare epilepsies is critical for optimization of Epidiolex treatment. Providers should differentiate Epidiolex from nonapproved CBD products and set expectations for the therapeutic effect and safety/tolerability of Epidiolex. Initial target dose and titration rate should be individualized by baseline variables, prior response to antiseizure medications, and therapeutic goals. Awareness of strategies to manage adverse events and concomitant medications, including drug-drug interactions, is critical. Tracking response to the maximum tolerated dose is an important measure of effectiveness. These consensus recommendations provide real-world experience from neurology HCPs with experience in prescribing Epidiolex and can inform optimal use of Epidiolex for the treatment of seizures associated with LGS, DS, and TSC. PLAIN LANGUAGE SUMMARY: Epidiolex® (cannabidiol) is approved for treating seizures in Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex. Although healthcare professionals have experience in treating patients with Epidiolex, there is a need for better understanding of dosing, drug interactions, and safety of this drug. Therefore, a group of epilepsy experts developed guidelines for best practices in Epidiolex treatment. Two main areas were identified: overcoming barriers to starting Epidiolex and considerations related to Epidiolex dosing. Within these areas, topics, including correct disease identification, managing adverse events, and determining individualized dose, were discussed. These guidelines provide real-world experience to inform optimal Epidiolex use.