Malaria remains one of the world's most prevalent tropical diseases with high mortality, morbidity, and socioeconomic impacts. Current antimalarials are mostly potent blood schizontocidals acting against erythrocytic stages that cause clinical symptoms, but the clinically silent pre-erythrocytic liver stage (LS) of Plasmodium spp.—which obligatorily precedes blood stages—represents a critical potential drug target. Inhibiting LS development can achieve true causal prophylaxis, interrupt transmission (as it depends on gametocytes from post-liver stage red blood cells), and reduce drug resistance risk due to the low number of hepatic forms. However, developing LS-targeting drugs is challenging due to Plasmodium LS biology and inherent technical study difficulties. Recent proteome and transcriptome analyses revealed LS-specific proteins (including those in the type II fatty acid synthesis [FAS-II] pathway) and overrepresented pathways (redox metabolism, tricarboxylic acid cycle, electron transport system, etc.). Rodent malaria models (e.g., P. berghei, P. yoelii) lack latent hypnozoites (present in P. vivax, P. ovale, causing relapses), limiting translational relevance. Most known LS inhibitors originate from traditional medicinal chemistry programs (largely 8-aminoquinolines) with limited chemical diversity. Recently, efforts to find novel leads have expanded to computational chemistry, natural product chemistry, and drug repurposing. This review provides an overview of inhibitors targeting the LS, with special emphasis on structure-activity relationships (SARs) and recent developments in the field.