A) Background and Objectives: Generic versions of drug are very interesting component of the pharmaceutical market. They can only be produced after a patent expire of the branded drug. Generic substitution in several countries has become a common practice. Besides, it is considered as a major cost minimizing strategy meant to contain pharmaceutical expenditure without compromising healthcare quality. However, the safety and quality issues of generic products are of top concerns of general practitioners and health work professionals. According to the Palestinian pharmacy practice legislation, community pharmacists are not permitted to change or substitute prescribed medicines without the consent of the prescribing physician. In the current study we would like to shed light on the rational of generic medicine use and to explore the criteria that Palestinian pharmacists based on for generic substitution. This study will help policy makers to implement suitable regulations regarding drug substitution policy to maximize the benefits on the patients and the Palestinian pharmaceutical practice. This study aimed to investigate community pharmacist's knowledge, attitudes and practices toward generic medicines in Palestine. B) Methods: This study was a cross-sectional observational study employing a self-administered questionnaire. The questionnaire was of four main sections: demographic and practice details of the participants, knowledge, attitudes and the influencing factors related to selection and dispensing of generic medicines. Using Raosoft sample size calculator the sample size was estimated to be 280 pharmacists. In order to minimize erroneous results and to increase the study reliability, the target sample size was set to be about 300 pharmacists. A convenience sampling technique was implemented in this study in which the data collection form was distributed in West Bank- Palestine among a set of practicing pharmacists. Mann-Whitney-U or Kruskal-Wallis tests were used to comparison of different issues as appropriate. P-values of < 0.05 were considered significant. C) Findings: A total of 302 community pharmacists were interviewed, slightly more than half were males (52.3%). The mean knowledge score of participants regarding generic medicines was (5.91 ± 1.27) where the highest score was 8 of 10. Knowledge score was not significantly associated by any of the socio-demographic characteristics. Our data showed that most of included pharmacists in the study (95.4%) agreed that health authorities should implement bioequivalence policies prior to marketing approval of generics, while 87.4% of participants agreed that they should be given the right to substitute generics and the majority (62.3%) support generic substitution for brand name drugs in all cases when a generic is available The main two factors affect pharmacists' selection and dispensing of generic medicines are personal faith in the product (86.1%) and cost effectiveness of generic medicines (84.1%). D) Conclusions: Generic medicines substitution among pharmacists is widespread and prevalent. Our data found that participant pharmacists in Palestine had basic knowledge with regards to generic medicine. However, their knowledge score pertaining the technical and regulatory aspects of bioequivalence and pharmacokinetic parameters in particular was insufficient.