Autophagy is a cell-protective and degradative process that recycles damaged and long-lived cellular components. Cancer cells are thought to take advantage of autophagy to help them to cope with the stress of tumorigenesis; thus targeting autophagy is an attractive therapeutic approach. However, there are currently no specific inhibitors of autophagy. ULK1, a serine/threonine protein kinase, is essential for the initial stages of autophagy, and here we report that two compounds, MRT67307 and MRT68921, potently inhibit ULK1 and ULK2 in vitro and block autophagy in cells. Using a drug-resistant ULK1 mutant, we show that the autophagy-inhibiting capacity of the compounds is specifically through ULK1. ULK1 inhibition results in accumulation of stalled early autophagosomal structures, indicating a role for ULK1 in the maturation of autophagosomes as well as initiation. Background: Autophagy is an intracellular lysosomal degradation pathway implicated in many diseases, but there are currently no specific autophagy inhibitors. Results: Small molecule inhibition of ULK1, the upstream autophagy initiating kinase, blocks autophagosome initiation and maturation. Conclusion: ULK1 plays a role in autophagosome maturation as well as initiation. Significance: ULK1 can be targeted to block autophagy for disease therapy.