Although the worms may not be universally accepted as having a direct relevance for AD pathology, they are well suited for validation of target A toxicity in vivo [12,21]. The absence of endogenous A production in the worms offers an opportunity to find a direct role of the A involvement in pathological behaviors [22]. In addition, predominantly intracellular expression of A provides another tool to address specific roles of intracellular A in relation to its toxicity. Substantial evidence implicates intracellular A oligomers in early events related to AD [16]. Intracellular A has also been observed in human brain neurons [23] and in triple transgenic AD mouse models, where its accumulation preceded neurofibrillary tangle formation [24]. This evidence supports the notion that A toxicity assayed in the worm model reflects A toxicity in mammalian neurons. A recent study indicates that the transgenic C. elegans model may be generally relevant to the proteotoxicity underlying neurodegenerative diseases [25]. Additionally, the strain has been used to investigate the role of insulin-like signaling and heat-shock factor in A proteotoxicity [26,27], providing excellent examples for the relevance of the C. elegans model to AD. There are several advantages of C. elegans over the mouse model for initial drug screening and target characterization. First, there are highly conserved biochemical pathways between worms and humans. Second, established transgenic mutant linking of human A expression with pathological behavioral phenotypes are easy to score. The worms have a relatively low cost of cultivation because of their small size, rapid life cycle, and short life span [28], which allow screening of thousands of animals over multiple generations on microtiter plates. The simple structure of its nervous system, consisting of only 302 neurons in an adult nematode, makes it valuable for screening drugs against age-associated neurodegeneration and the ease of genetic manipulations, which is evident in the availability of mutants and application of RNA interference (RNAi) knockdown. Several examples illustrate the power of C. elegans in screening for new drugs [29], including many known human drugs [30,31]. Some lead molecules originating from worm-based screening assays are in advanced stages of drug discovery [11]. Using the C. elegans model in the past years, we have uncovered effects of natural compounds on extension of the worms' life span; [32] on a stress response protein, the small heat-shock protein hsp-16.2; [33] on age-related behavioral declines; [34] on muscle degeneration; [35] and on A-expression-induced pathological behaviors [22]. Most of those experiments would be difficult and might be impossible to perform in mice. In this chapter, we describe methods we have employed for compound screening and pharmacological evaluations of potential AD drugs using the C. elegans model.