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Thrombocytopenia is one of the most commonly observed drug-induced adverse hematologic toxicities in the clinic. Therefore, in vitro and in vivo evaluations of effect of drugs on platelets are an important component in preclinical safety assessment in drug development. To date, a number of mechanisms have been identified to be associated with drug-mediated thrombocytopenia. Amongst these, some are conserved across species whereas others are not. Therefore, a case-by-case approach is needed to assess drug-induced thrombocytopenia at preclinical stages to understand translatability to humans. The present chapter reviews mechanisms in drug-mediated thrombocytopenia with a focus on nonimmune (direct myelotoxicity) as well as immune-mediated thrombocytopenia by both small and large molecule therapeutics. Several in vitro and in vivo models as well as challenges in assessing drug-mediated thrombocytopenia in preclinical stages will also be discussed.