Tomato leaf curl New Delhi virus (ToLCNDV) is a bipartite begomovirus that has been a serious threat to horticultural crops grown worldwide. The virus primarily affects economically important crops of solanaceous and cucurbitaceous families, such as tomato, peppers, cucurbits, etc., causing severe yield losses. ToLCNDV is transmitted efficiently by the whitefly, Bemisia tabaci, which has been a reported vector globally. Factors that contribute to the disease spread include global distribution of the vector population, temperature, humidity, and seasonal changes, which also affect the vector dynamics. First reported in India, the virus is mainly present in Asia, Europe, and the Middle East, causing sporadic economic losses. The infection involves virus and host plant interactions, where the bipartite genome of the virus, upon entering the host, encodes several essential proteins for replication, movement, and suppression of the host’s defense mechanisms. The host plant develops characteristic symptoms, including leaf curling, vein thickening, chlorosis, and stunted growth. These symptoms often lead to reduced or complete loss of quality and yield loss. To mitigate the virus and overcome the impact on the global horticulture production, it is essential to understand its molecular characteristics, functions, and interactions with the host. This chapter discusses the epidemiological and pathophysiological aspects of ToLCNDV infection in horticultural crops, focusing on the interaction between the virus, vector, and host at the cellular and molecular levels.