OBJECTIVES:  to assess the knowledge of health professionals about epidemiological and national regulatory issues concerning rare diseases (RD) and access to orphan drugs. METHODS: This paper reports some of the results from an ongoing KAP study on rare diseases and orphan drugs in the Republic of Serbia (RS). A prospective cross-sectional study was conducted from May to June 2013, on a convenient sample of licensed pharmacists and physicians from two, large cities` and its suburbies in the central parts of RS. A specially designed KAP instrument in a form of three-part questionnaire was applied and these results were related to the assessment of concerning knowledge (8 multiple-choice questions) and self-assessment of the participants (one question).   RESULTS: The study population included 214 health workers (151 pharmacists and 63 physicians); the average age of participants was 40.80±9.45 and the average years of professional practice was 13.14 ± 9.68. Majority of the participants (57%) knew the true prevalence of RD and slightly less than third of the samples (26.2%) responded correctly to the question of the extent of European  population suffering from RD. There are major differences in regulatory knowledge about access to treatment for rare diseases, as participants answered correctly in a wide range of 21% to 67.4%. Most of the health professionals self-estimated that possessed little (31.3%) or enough (43.5%) knowledge related to general epidemiological and legislative issues concerning RD and orphan drugs. The average level of overall knowledge assessment for all questions and self-assessmentin general was 3.53 ± 1.58 and 2.04± 0.87 respectively. CONCLUSIONS: The majority of respondents estimated that possess less  knowledge on RD (general information) and drugs to treat RD, or insufficiently. The average level of respondents’ knowledge on RD and drugs to treat RD was below the average.